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Popular Reports / nephrology

This report is written by MaltSci based on the latest literature and research findings

What is the role of podocytes in kidney disease? ​

Abstract ​

Podocytes are specialized epithelial cells crucial for the kidney's glomerular filtration barrier, and their injury is increasingly recognized as a key event in the pathogenesis of various kidney diseases, including diabetic nephropathy and focal segmental glomerulosclerosis. This review provides an overview of podocyte structure and function, highlighting their role in maintaining glomerular integrity. We explore the mechanisms of podocyte injury, which can arise from metabolic stress, mechanical strain, and inflammation, leading to proteinuria and glomerulosclerosis. The clinical significance of proteinuria as an indicator of kidney dysfunction is discussed, alongside the relationship between podocyte loss and disease progression. Current therapeutic strategies targeting podocytes, including pharmacological interventions and regenerative medicine, are examined for their potential to restore podocyte function and slow disease progression. Finally, we outline future research directions, emphasizing the need for novel biomarkers and therapeutic targets to enhance our understanding and treatment of podocyte-related kidney diseases. By elucidating the complex biology of podocytes, this review aims to contribute to the development of innovative strategies for managing kidney diseases.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Podocyte Structure and Function
    • 2.1 Morphological Characteristics
    • 2.2 Role in Glomerular Filtration
  • 3 Mechanisms of Podocyte Injury
    • 3.1 Diabetic Nephropathy
    • 3.2 Focal Segmental Glomerulosclerosis (FSGS)
    • 3.3 Other Causes of Podocyte Injury
  • 4 Consequences of Podocyte Dysfunction
    • 4.1 Proteinuria and its Clinical Significance
    • 4.2 Progression to Glomerulosclerosis
  • 5 Therapeutic Approaches Targeting Podocytes
    • 5.1 Pharmacological Interventions
    • 5.2 Regenerative Medicine Strategies
  • 6 Future Directions in Podocyte Research
    • 6.1 Emerging Biomarkers
    • 6.2 Novel Therapeutic Targets
  • 7 Conclusion

1 Introduction ​

Podocytes are highly specialized epithelial cells that play a pivotal role in the kidney's glomerular filtration barrier. Their unique morphology, characterized by interdigitating foot processes that form filtration slits, is essential for the selective permeability of the glomerular membrane. Recent advancements in the understanding of podocyte biology have underscored their critical functions not only in maintaining renal homeostasis but also in the pathogenesis of various kidney diseases. Podocyte injury is increasingly recognized as a key event leading to proteinuria, a hallmark of kidney dysfunction, and contributes to the progression of glomerulosclerosis and chronic kidney disease (CKD) [1][2][3].

The significance of podocytes extends beyond their structural role; they are involved in various cellular processes that ensure glomerular integrity. Disruption of podocyte function can result from numerous factors, including metabolic disorders, mechanical stress, and inflammatory responses, leading to significant clinical consequences. Understanding the mechanisms underlying podocyte injury is crucial for developing targeted therapeutic strategies. Recent studies have identified diverse pathways involved in podocyte damage, including oxidative stress, cytoskeletal dysregulation, and lysosomal dysfunction [4][5][6]. This highlights the need for a comprehensive review of the current knowledge regarding podocyte biology, injury mechanisms, and potential therapeutic interventions.

This review aims to provide an in-depth overview of the role of podocytes in kidney disease. We will first discuss the structural and functional characteristics of podocytes, emphasizing their contributions to glomerular filtration (Section 2). Subsequently, we will explore the various mechanisms of podocyte injury associated with conditions such as diabetic nephropathy and focal segmental glomerulosclerosis (FSGS) (Section 3). The consequences of podocyte dysfunction, particularly the clinical significance of proteinuria and its relationship to glomerulosclerosis, will be addressed in Section 4.

In Section 5, we will examine current therapeutic approaches targeting podocytes, including pharmacological interventions and regenerative medicine strategies. The potential of these therapies to restore podocyte function and mitigate kidney disease progression will be discussed. Lastly, we will outline future directions in podocyte research, focusing on emerging biomarkers and novel therapeutic targets (Section 6). By synthesizing current findings and highlighting critical areas for further investigation, this review seeks to elucidate the importance of podocytes in kidney disease management and their potential as therapeutic targets.

In conclusion, the study of podocytes is essential for advancing our understanding of kidney diseases and developing innovative treatment strategies. As the burden of kidney disease continues to rise globally, insights into podocyte biology and pathology will be instrumental in addressing this pressing health challenge.

2 Podocyte Structure and Function ​

2.1 Morphological Characteristics ​

Podocytes are highly specialized epithelial cells located in the glomerulus of the kidney, playing a crucial role in maintaining the glomerular filtration barrier. Their unique morphology is characterized by an intricate network of foot processes that interconnect via slit diaphragms. This structure is essential for the selective filtration of plasma, ensuring that blood components are separated from urine. The architecture of podocytes not only facilitates filtration but also serves as a critical point of interaction with neighboring cells and the extracellular matrix, which is vital for their functional integrity[1].

The morphological characteristics of podocytes include a cell body from which extend numerous foot processes (FPs). These FPs interdigitate with those from adjacent podocytes, forming narrow slit diaphragms that act as a selective barrier to proteins and other macromolecules. This specialized structure is maintained by a complex cytoskeletal framework primarily composed of actin filaments, which is critical for the stability and function of the podocyte[7]. The integrity of this architecture is fundamental to podocyte function; any disruption can lead to significant consequences for kidney health.

In terms of their role in kidney disease, podocytes are particularly vulnerable to various types of injury, including genetic mutations, mechanical stress, metabolic disorders, and inflammation. Such injuries can lead to a series of pathological changes, including hypertrophy, detachment, and apoptosis, ultimately resulting in proteinuria and progressive kidney disease[4]. For instance, podocyte injury is a pivotal event in the progression of conditions such as diabetic kidney disease, where the loss of podocyte function correlates with the onset of proteinuria and glomerulosclerosis[3].

Recent research has also highlighted the importance of lysosomal function and lipid metabolism in podocyte health. Dysfunctional lysosomes can disrupt autophagic processes, which are essential for podocyte survival, especially under pathological conditions[2]. Furthermore, excessive lipid accumulation in podocytes can lead to cellular dysfunction, characterized by mitochondrial oxidative stress and cytoskeletal remodeling, which further exacerbates podocyte injury[6].

In summary, podocytes are integral to the kidney's filtration system, and their unique morphological features are crucial for maintaining the filtration barrier. Their susceptibility to injury and the resulting cellular changes play a significant role in the pathogenesis of various kidney diseases, emphasizing the need for targeted therapeutic strategies to protect and restore podocyte function in the context of renal pathologies[1][3][7].

2.2 Role in Glomerular Filtration ​

Podocytes are highly specialized epithelial cells located in the glomerulus of the kidney, playing a crucial role in maintaining the integrity of the glomerular filtration barrier (GFB). This barrier is essential for the selective filtration of blood to form urine, allowing the passage of water and small solutes while preventing the loss of larger molecules such as proteins. The unique architecture of podocytes, characterized by an intricate network of foot processes interconnected by slit diaphragms, serves as a critical selective filter for plasma ultrafiltration (Riedmann et al., 2023; Loreth et al., 2025).

In the context of kidney disease, podocytes are pivotal due to their involvement in both the pathogenesis and progression of various proteinuric kidney disorders. Damage to podocytes can result from intrinsic factors, such as genetic mutations, or extrinsic factors, including immune-mediated injuries. This damage often leads to proteinuria, a condition where excess proteins leak into the urine, which is an early indicator of chronic kidney disease (CKD) (Jiang et al., 2023; Brinkkoetter et al., 2013).

Recent studies have established that podocyte injury is a major cause of significant albuminuria and nephrotic syndrome. The loss of podocytes has been identified as a critical factor in the development of glomerulosclerosis and progressive proteinuric kidney disease (Brinkkoetter et al., 2013). Furthermore, podocytes are not only targets of immune responses but also exhibit immune cell-like characteristics, participating in both innate and adaptive immunity. This dual role highlights their importance in mediating glomerular injury and suggests that they could be potential therapeutic targets for CKD (Jiang et al., 2023).

The regulation of podocyte function is complex and influenced by various signaling pathways and environmental factors. For instance, podocytes respond to harmful stimuli by re-entering the cell cycle, a process that can lead to structural and functional impairments, such as foot process effacement and subsequent detachment from the glomerular basement membrane (Zhang & Guo, 2025). This detachment contributes to the progression of kidney diseases and is a hallmark of glomerular damage (Tharaux & Huber, 2012).

Moreover, podocytes play a role in cellular communication within the glomerulus. They interact with other glomerular cells, including endothelial cells and mesangial cells, to maintain glomerular health. Disruption of this communication can exacerbate kidney disease progression (Gujarati et al., 2024). Understanding the mechanisms of podocyte injury and their contributions to glomerular diseases is essential for developing targeted therapies aimed at preserving podocyte integrity and function, thereby mitigating proteinuria and delaying the progression of kidney diseases (Meliambro et al., 2024).

In summary, podocytes are integral to kidney function and health, serving as both structural components of the glomerular filtration barrier and active participants in the immune response. Their injury and loss are central to the pathogenesis of various kidney diseases, emphasizing the need for continued research into podocyte biology and therapeutic strategies targeting these critical cells.

3 Mechanisms of Podocyte Injury ​

3.1 Diabetic Nephropathy ​

Podocytes are specialized epithelial cells that play a crucial role in maintaining the integrity of the glomerular filtration barrier (GFB) in the kidneys. Their structural and functional integrity is vital for proper kidney function, and damage to these cells is a significant contributor to various kidney diseases, particularly diabetic nephropathy (DN).

In diabetic nephropathy, podocyte injury manifests through several mechanisms, leading to proteinuria, which is a hallmark of kidney damage. Podocytes are terminally differentiated cells with limited capacity for regeneration, making them particularly vulnerable to metabolic stressors associated with diabetes, such as high glucose levels. Elevated glucose concentrations can induce metabolic shifts in podocytes, prompting them to switch from mitochondrial oxidative phosphorylation to glycolysis, which can result in lactic acidosis and further compromise their function [8].

Morphologically, podocyte injury in DN is characterized by effacement of foot processes, hypertrophy, and a shift from an epithelial to a mesenchymal phenotype, often referred to as epithelial-mesenchymal transition (EMT). This transition contributes to the loss of podocyte integrity and function, leading to increased permeability of the GFB and subsequent proteinuria [[pmid:28748185],[pmid:27053072]]. The effacement of podocyte foot processes is particularly critical, as these structures are essential for the formation of slit diaphragms that regulate glomerular permeability [8].

The pathogenesis of podocyte injury in DN also involves epigenetic alterations and DNA damage. Studies indicate that epigenetic changes, including DNA methylation, are associated with podocyte dysfunction and are implicated in the progression of chronic kidney disease, including DN [9]. Moreover, high glucose conditions can lead to increased DNA damage in podocytes, which is believed to exacerbate their injury and loss [9].

Mitochondrial dysfunction is another critical factor in podocyte injury. Mitochondria are essential for cellular energy production and signaling pathways, and their impairment has been linked to the progression of diabetic nephropathy [10]. Understanding the dynamics of podocyte mitochondrial function is crucial, as it may provide insights into potential therapeutic targets aimed at protecting podocytes from injury [10].

In addition to metabolic and structural changes, podocyte death via various forms of programmed cell death (PCD) such as apoptosis, autophagy, and necroptosis is a significant aspect of podocyte pathology in DN [[pmid:39018872],[pmid:37828444]]. The dysregulation of these cell death pathways contributes to the loss of podocytes and the subsequent decline in kidney function.

Furthermore, recent research highlights the interaction between podocytes and immune cells, particularly macrophages, in the diabetic kidney. This cross-talk can influence podocyte survival and function, further complicating the disease progression [11].

Overall, podocytes are central to the pathophysiology of diabetic nephropathy. Their injury and loss are pivotal events that lead to the development of proteinuria and contribute to the progression of chronic kidney disease. Understanding the mechanisms underlying podocyte injury is crucial for developing targeted therapies aimed at preserving podocyte function and preventing the progression to end-stage renal disease.

3.2 Focal Segmental Glomerulosclerosis (FSGS) ​

Podocytes are specialized epithelial cells that play a crucial role in maintaining the integrity of the glomerular filtration barrier in the kidneys. They are essential for proper filtration function, and their injury is a key factor in the pathogenesis of focal segmental glomerulosclerosis (FSGS), a common glomerular disorder characterized by significant proteinuria and progressive loss of renal function.

In healthy conditions, podocytes maintain a highly coordinated mitochondrial quality control system, which includes antioxidant defenses, mitochondrial dynamics (fusion, fission, and mitophagy), and mitochondrial biogenesis. This system is vital for the sophisticated structure and function of podocytes. However, under pathological conditions associated with FSGS, podocytes experience mitochondrial dysfunction, oxidative stress, and disturbances in mitochondrial dynamics and biogenesis. This dysfunction can be exacerbated by mutations in mitochondrial DNA and mitochondria-related genes, which are strongly linked to FSGS (Li et al., 2023) [12].

The injury to podocytes can result from various factors, including mechanical stress, chemical toxicity, inflammation, and genetic predispositions. For instance, podocytes face mechanical challenges such as stretch and shear stress due to pulsatile blood flow, which can lead to cytoskeletal impairments and contribute to podocyte dysfunction and detachment. This is particularly relevant in the context of FSGS, where podocyte injury can lead to structural changes such as foot process effacement and ultimately result in proteinuria (Feng et al., 2018) [13].

The pathogenesis of FSGS is multifactorial and can involve both primary intrinsic podocyte injury and secondary responses to various stimuli. Genetic factors, such as mutations in structural genes of podocytes and variants in the apolipoprotein L1 gene, have been identified as significant contributors to FSGS, especially in certain populations (Fogo, 2015) [14]. Moreover, soluble factors and immune-mediated processes can also promote podocyte injury and disease progression (Campbell & Tumlin, 2018) [15].

In summary, podocytes are integral to kidney function, and their injury is a central feature in the development and progression of FSGS. Understanding the mechanisms of podocyte injury, including mitochondrial dysfunction, mechanical stress, and genetic susceptibility, is crucial for developing targeted therapeutic strategies to manage and treat FSGS effectively. As research progresses, new insights into podocyte biology and pathology may pave the way for innovative treatments aimed at protecting these vital cells and improving outcomes for patients with FSGS.

3.3 Other Causes of Podocyte Injury ​

Podocytes are highly specialized epithelial cells that play a crucial role in maintaining the integrity of the glomerular filtration barrier in the kidneys. They are terminally differentiated cells that form a complex network of foot processes, which interdigitate to create filtration slits essential for selective permeability. Injury to podocytes is a pivotal event in the pathogenesis of various kidney diseases, particularly those characterized by proteinuria, such as diabetic nephropathy, focal segmental glomerulosclerosis, and membranous nephropathy [6].

Mechanisms of podocyte injury are multifaceted and can be broadly categorized into several pathways. One of the primary mechanisms involves mitochondrial dysfunction, which is increasingly recognized as a significant contributor to podocyte injury. Mitochondrial oxidative stress leads to the accumulation of reactive oxygen species (ROS), resulting in cellular damage and apoptosis [16]. Excessive ROS generation can overwhelm the antioxidant defenses, thereby promoting oxidative damage to podocytes and influencing cell death [16]. Furthermore, disturbances in mitochondrial bioenergetics are linked to insulin resistance and inflammatory responses, which can exacerbate podocyte injury [10].

Another critical factor contributing to podocyte injury is lipid metabolism. Disruption of lipid homeostasis within podocytes can lead to lipotoxicity, characterized by excessive lipid accumulation, which further results in mitochondrial oxidative stress, cytoskeletal remodeling, and ultimately, podocyte hypertrophy and detachment [6]. This lipotoxicity is associated with various proteinuric kidney diseases, indicating that targeting podocyte lipid metabolism may offer novel therapeutic strategies [6].

In addition to metabolic disturbances, podocytes are susceptible to genetic factors and environmental triggers. Genetic mutations in podocyte-expressed genes have been linked to various forms of nephrotic syndrome and other podocytopathies. Environmental factors such as immune-related conditions, infections, and mechanical stress also play a significant role in podocyte injury [17]. For instance, the binding of circulating autoantibodies to podocyte proteins can activate complement pathways, leading to further damage and proteinuria [18].

Moreover, podocytes are terminally differentiated and possess limited regenerative capacity. This characteristic means that when podocytes are damaged, they often cannot adequately recover, leading to chronic kidney disease (CKD) and end-stage renal disease (ESRD) [7]. The inability of podocytes to proliferate in response to injury complicates the recovery process and underscores the importance of understanding the mechanisms of podocyte injury for developing effective therapeutic interventions.

Overall, the role of podocytes in kidney disease is critical, as they are integral to maintaining the glomerular filtration barrier. The mechanisms underlying podocyte injury are diverse and include mitochondrial dysfunction, lipid metabolism disturbances, genetic mutations, and environmental factors. Addressing these mechanisms is essential for advancing therapeutic strategies aimed at preserving podocyte function and mitigating the progression of kidney diseases.

4 Consequences of Podocyte Dysfunction ​

4.1 Proteinuria and its Clinical Significance ​

Podocytes play a crucial role in maintaining the integrity of the glomerular filtration barrier, which is essential for proper kidney function. These specialized epithelial cells are located in the kidney glomerulus and are responsible for the selective filtration of proteins, preventing their loss into the urine. When podocytes become dysfunctional, the consequences can be severe, leading to a range of kidney diseases characterized by proteinuria, which is the presence of excess protein in the urine.

The dysfunction of podocytes can result from various factors, including genetic mutations, environmental stressors, and metabolic disorders such as diabetes mellitus. In diabetic kidney disease, for instance, the structural and functional alterations in podocytes contribute significantly to the development of proteinuria and the progression of diabetic nephropathy (DN). Histological changes observed in DN include podocyte hypertrophy, foot process effacement, and eventual loss of podocytes, which collectively compromise the glomerular filtration barrier and lead to increased protein leakage into the urine (Kumar et al. 2014; Lin & Susztak 2016).

Proteinuria is not merely a laboratory finding; it is a clinical hallmark of glomerular injury and is associated with worse renal outcomes. The extent of proteinuria is often correlated with the severity of kidney damage and can serve as a prognostic indicator for disease progression. For instance, studies have shown that the absolute number of podocytes is predictive of glomerular function, and their loss is a hallmark of various glomerular diseases, including focal segmental glomerulosclerosis and minimal change disease (Brinkkoetter et al. 2013; Meliambro et al. 2024).

Furthermore, the development of proteinuria signifies a breach in the glomerular filtration barrier, leading to systemic consequences such as hypoalbuminemia, edema, and hyperlipidemia, which are characteristic of nephrotic syndrome (Smoyer & Mundel 1998). The chronic presence of protein in the urine can also induce tubulointerstitial fibrosis, further aggravating kidney dysfunction and increasing the risk of progression to end-stage renal disease (Zhang & Guo 2025).

In summary, podocytes are integral to the functioning of the kidney, and their injury leads to significant clinical consequences, primarily through the development of proteinuria. This condition serves as both a symptom and a predictor of kidney disease progression, highlighting the importance of targeting podocyte health in therapeutic strategies for managing kidney diseases. The focus on understanding the molecular and cellular events leading to podocyte dysfunction continues to be a critical area of research, aiming to develop novel therapies that can mitigate podocyte injury and preserve kidney function (Hejazian et al. 2023; Liu et al. 2022).

4.2 Progression to Glomerulosclerosis ​

Podocytes are specialized epithelial cells located in the glomeruli of the kidneys, playing a crucial role in maintaining glomerular structure and function. They form part of the glomerular filtration barrier, which is essential for filtering blood and preventing proteinuria. The health and integrity of podocytes are critical, as their dysfunction is closely linked to various forms of kidney disease, particularly proteinuric glomerular diseases.

Podocyte injury is a significant contributor to the pathogenesis of kidney diseases, including diabetic kidney disease, focal segmental glomerulosclerosis (FSGS), and minimal change disease. When podocytes are damaged, their ability to maintain the filtration barrier is compromised, leading to protein leakage into the urine, a condition known as proteinuria. This initial loss of podocyte function can trigger a cascade of pathological changes, ultimately resulting in progressive glomerulosclerosis and end-stage renal disease (ESRD) [3][19][20].

The mechanisms underlying podocyte dysfunction include various intrinsic and extrinsic factors, such as metabolic disturbances in diabetes, inflammatory responses, and genetic predispositions. For instance, in diabetic kidney disease, podocytes experience metabolic stress due to high glucose levels, leading to alterations in cellular signaling pathways that govern podocyte health. This metabolic derangement results in podocyte apoptosis, effacement of foot processes, and a reduction in podocyte number, all of which contribute to the deterioration of the glomerular filtration barrier [3][21].

As podocyte injury progresses, the loss of these cells leads to a compensatory response from the remaining podocytes, which can further exacerbate the situation. The remaining podocytes may undergo hypertrophy and stress, leading to a vicious cycle of injury and loss. Ultimately, this results in glomerulosclerosis, characterized by the accumulation of extracellular matrix and scarring within the glomeruli, which impairs kidney function and can lead to chronic kidney disease (CKD) [22][23].

Moreover, recent studies have highlighted the immune response associated with podocyte injury, revealing that podocytes not only serve as structural components but also exhibit immune cell-like characteristics. They can participate in both innate and adaptive immunity, further complicating the pathophysiology of kidney diseases [22]. This immune-mediated injury is particularly evident in diseases like lupus nephritis and membranous nephropathy, where podocytes are targeted by immune responses, leading to their dysfunction and subsequent progression to glomerulosclerosis [22].

In summary, podocytes play a pivotal role in kidney health, and their dysfunction is a critical factor in the progression of glomerular diseases. Understanding the mechanisms of podocyte injury and loss is essential for developing targeted therapies aimed at preserving podocyte function and preventing the progression to glomerulosclerosis and ESRD [24].

5 Therapeutic Approaches Targeting Podocytes ​

5.1 Pharmacological Interventions ​

Podocytes are specialized epithelial cells located in the glomerulus, playing a critical role in maintaining the glomerular filtration barrier. Their injury is a significant factor in the pathogenesis of various kidney diseases, particularly those characterized by proteinuria, such as diabetic kidney disease, focal segmental glomerulosclerosis, and minimal change disease. The loss of podocytes directly correlates with the severity of proteinuria and the progression of chronic kidney disease (CKD) [25].

The primary functions of podocytes include the regulation of glomerular permeability and the maintenance of the structural integrity of the filtration barrier. They achieve this through their unique morphology, characterized by foot processes that interdigitate to form slit diaphragms. This architecture is essential for filtering blood while retaining proteins and cells [26]. However, podocytes have a limited capacity for self-repair due to their terminally differentiated nature, making them particularly susceptible to injury from various factors, including metabolic stress, inflammation, and genetic mutations [27].

Therapeutic approaches targeting podocytes have gained attention due to their central role in kidney disease. Current pharmacological interventions primarily focus on preventing podocyte injury and promoting their repair. Several strategies have emerged:

  1. Histone Deacetylase Inhibitors: These agents have shown potential in protecting podocytes from injury by modulating inflammatory responses, apoptosis, and mitochondrial function. The pharmacological targeting of HDAC-mediated epigenetic processes could represent a novel therapeutic avenue for chronic kidney disease [4].

  2. Actin Cytoskeleton Regulators: The integrity of the podocyte actin cytoskeleton is crucial for its function. Therapeutics that target actin-regulating proteins aim to restore podocyte architecture and function, thereby enhancing glomerular filtration barrier integrity [28].

  3. Mitochondrial Protection: Mitochondrial oxidative stress is implicated in podocyte injury. Antioxidants that can mitigate oxidative damage may offer a therapeutic benefit in preserving podocyte function [16].

  4. Lipid Metabolism Modulators: Dysregulation of lipid metabolism in podocytes has been linked to cellular dysfunction and injury. Targeting lipid accumulation and its downstream effects may provide a novel strategy for managing proteinuric kidney diseases [6].

  5. Cell Cycle Regulation: Understanding the mechanisms that lead to podocyte re-entry into the cell cycle, which can result in further injury and apoptosis, presents another therapeutic target. Interventions that prevent aberrant cell cycle progression could help maintain podocyte integrity [29].

  6. Stem Cell Therapies: Mesenchymal stem cells (MSCs) have been explored for their regenerative potential in podocyte injury. These cells can provide paracrine factors that support podocyte survival and function, offering a promising avenue for treatment [30].

  7. Gene Therapy: With the identification of genetic mutations associated with podocytopathies, gene therapy may emerge as a targeted approach to correct specific defects in podocyte function [17].

In conclusion, podocytes are essential for maintaining kidney function, and their injury is a critical event in the progression of kidney diseases. A variety of therapeutic strategies targeting podocyte biology, including pharmacological interventions, stem cell therapies, and gene therapy, are being investigated to mitigate podocyte injury and improve outcomes in patients with kidney disease [24][31].

5.2 Regenerative Medicine Strategies ​

Podocytes are highly specialized and terminally differentiated epithelial cells that play a critical role in maintaining the integrity of the glomerular filtration barrier in the kidney. They are integral to the filtration process and their injury is a significant contributor to various forms of kidney disease, particularly those characterized by proteinuria, such as diabetic kidney disease and focal segmental glomerulosclerosis. The loss or dysfunction of podocytes can lead to increased permeability of the glomerular barrier, resulting in proteinuria, which is a hallmark of kidney disease and can progress to end-stage renal failure if not addressed.

In terms of therapeutic approaches targeting podocytes, there has been a notable shift towards precision-based treatments aimed at directly addressing podocyte injury. Traditional therapies have often relied on systemic immunosuppressive agents, which, while beneficial, are associated with numerous side effects due to their nonspecific action. Recent advances in our understanding of the mechanistic basis of podocyte injury have led to the identification of specific pathways and molecular targets that can be exploited for more targeted therapies. For instance, histone deacetylase (HDAC) inhibitors have been shown to protect against podocyte injury by regulating inflammation, apoptosis, and other cellular functions, suggesting a promising avenue for therapeutic intervention in proteinuric kidney diseases (Liu et al., 2020)[4].

Moreover, the exploration of regenerative medicine strategies is gaining traction in the context of podocyte-targeted therapies. This includes the use of stem cell-based approaches, such as mesenchymal stem cells (MSCs), which have demonstrated potential in repairing podocyte damage through their regenerative capabilities and paracrine effects, contributing to the preservation of podocyte function and integrity (Khalilpourfarshbafi et al., 2017)[30]. Additionally, the directed differentiation of human pluripotent stem cells into podocytes offers a promising strategy for generating podocytes for research and potential therapeutic applications, facilitating drug screening and modeling of podocyte diseases (Qian et al., 2019)[32].

Furthermore, the understanding of mitochondrial dysfunction in podocytes is emerging as a crucial factor in podocyte injury and subsequent kidney disease progression. Targeting mitochondrial health and bioenergetics may represent another innovative therapeutic strategy, as mitochondrial oxidative stress has been implicated in podocyte cell death and injury (Zhu et al., 2022)[16].

In summary, podocytes are central to kidney function and their injury is a critical event in the pathogenesis of various kidney diseases. The development of targeted therapies, including pharmacological agents and regenerative medicine strategies, holds promise for improving outcomes in patients with proteinuric kidney diseases. As research continues to uncover the intricate biology of podocytes, the potential for novel therapeutic interventions to mitigate podocyte injury and enhance kidney repair becomes increasingly optimistic.

6 Future Directions in Podocyte Research ​

6.1 Emerging Biomarkers ​

Podocytes are highly specialized epithelial cells located in the glomerulus of the kidney, playing a crucial role in maintaining the glomerular filtration barrier. Their structural integrity and function are vital for normal kidney operation, as they form an intricate network of foot processes interconnected by slit diaphragms, which serve as a selective filter for plasma ultrafiltration. The injury or loss of podocytes is recognized as a significant event in the progression of various kidney diseases, particularly those characterized by proteinuria, such as diabetic kidney disease, focal segmental glomerulosclerosis, and membranous nephropathy [2][3][5].

Podocyte injury can lead to several pathological processes, including proteinuria, glomerulosclerosis, and eventual loss of renal function. The mechanisms underlying podocyte injury are multifaceted, involving apoptosis, necroptosis, and cytoskeletal dysregulation, often exacerbated by metabolic disorders and inflammation [5][7]. Importantly, podocytes are terminally differentiated cells with limited regenerative capacity, making their preservation critical for kidney health [7].

Emerging research highlights the role of epigenetic modifications, such as those mediated by histone deacetylases (HDACs), in podocyte biology. These modifications can influence podocyte survival by regulating inflammation, apoptosis, and autophagy [4]. Additionally, mitochondrial dysfunction and oxidative stress have been implicated in podocyte injury, suggesting that targeting mitochondrial pathways may offer new therapeutic avenues [5][16].

Future directions in podocyte research are likely to focus on identifying novel biomarkers for early detection of podocyte injury and developing targeted therapies to prevent or mitigate podocyte damage. The advancement of stem cell technologies and kidney organoid models provides promising platforms for studying podocyte development and disease mechanisms [7][32]. Furthermore, understanding the lipid metabolism of podocytes and its association with kidney diseases may reveal new therapeutic strategies [6].

In summary, podocytes are integral to kidney function, and their dysfunction is a central feature of many kidney diseases. Continued research into the mechanisms of podocyte injury and potential biomarkers will be crucial for developing effective interventions in kidney disease management.

6.2 Novel Therapeutic Targets ​

Podocytes are specialized, terminally differentiated epithelial cells located in the glomeruli of the kidneys, playing a critical role in maintaining the glomerular filtration barrier. Their integrity is essential for proper kidney function, and damage to these cells is a key factor in the pathogenesis of various kidney diseases, particularly proteinuric kidney disorders, which account for a significant proportion of end-stage renal disease cases worldwide. Podocyte injury leads to proteinuria, a condition characterized by the abnormal presence of proteins in urine, which is a hallmark of glomerular diseases such as diabetic nephropathy, focal segmental glomerulosclerosis, and minimal change disease [24][27][33].

The recent understanding of podocyte biology has highlighted several novel therapeutic targets aimed at preventing podocyte injury and promoting their repair or regeneration. For instance, advancements in the identification of disease-causing genes and the pathways involved in podocyte dysfunction have opened avenues for precision-based treatment approaches. Therapeutic strategies are being developed that specifically target the podocytes to minimize systemic side effects associated with traditional therapies [24][31].

Among the promising directions in podocyte research are the exploration of epigenetic modifications, particularly the role of histone deacetylases (HDACs) in regulating podocyte function. Recent studies suggest that pharmacological targeting of HDAC-mediated epigenetic processes may provide new therapeutic options for chronic kidney disease by protecting podocytes from injury through the regulation of inflammation, apoptosis, and mitochondrial function [4].

Moreover, the metabolic health of podocytes, particularly lipid metabolism, is emerging as a significant area of interest. Disruptions in lipid metabolism within podocytes can lead to cellular dysfunction and contribute to the progression of proteinuric kidney diseases. Targeting these metabolic pathways may represent a novel therapeutic strategy to enhance podocyte resilience and function [6].

In addition, innovative drug delivery systems, such as ultrasmall polymeric nanocarriers, are being investigated for their ability to deliver therapeutic agents specifically to podocytes. This targeted approach could significantly improve the efficacy of treatments while reducing systemic exposure and associated side effects [34].

As research continues to evolve, the integration of findings from various fields, including molecular biology, regenerative medicine, and drug delivery technologies, will likely yield new insights and therapeutic strategies aimed at podocyte protection and repair. This multi-faceted approach underscores the importance of podocytes in kidney health and disease, paving the way for more effective interventions in managing kidney disorders.

7 Conclusion ​

Podocytes are integral components of the kidney's glomerular filtration barrier, and their health is crucial for maintaining renal function. The review highlights that podocyte injury is a central event in the progression of various kidney diseases, particularly those characterized by proteinuria, such as diabetic nephropathy and focal segmental glomerulosclerosis. The mechanisms of podocyte injury are multifaceted, involving metabolic disturbances, oxidative stress, genetic factors, and inflammatory responses. Current therapeutic approaches targeting podocytes, including pharmacological interventions and regenerative medicine strategies, show promise in preserving podocyte function and mitigating kidney disease progression. Future research directions should focus on identifying novel biomarkers for early detection of podocyte injury and developing targeted therapies aimed at specific pathways involved in podocyte health. Continued exploration of podocyte biology will be essential for advancing treatment options and improving outcomes for patients suffering from kidney diseases.

References ​

  • [1] Desiree Loreth;Wiebke Sachs;Catherine Meyer-Schwesinger. The Life of a Kidney Podocyte.. Acta physiologica (Oxford, England)(IF=5.6). 2025. PMID:40698593. DOI: 10.1111/apha.70081.
  • [2] Guangbi Li;Jason Kidd;Pin-Lan Li. Podocyte Lysosome Dysfunction in Chronic Glomerular Diseases.. International journal of molecular sciences(IF=4.9). 2020. PMID:32106480. DOI: 10.3390/ijms21051559.
  • [3] Jamie S Lin;Katalin Susztak. Podocytes: the Weakest Link in Diabetic Kidney Disease?. Current diabetes reports(IF=6.4). 2016. PMID:27053072. DOI: 10.1007/s11892-016-0735-5.
  • [4] Min Liu;Zhe Qiao;Yang Zhang;Ping Zhan;Fan Yi. Histone Deacetylases Take Center Stage on Regulation of Podocyte Function.. Kidney diseases (Basel, Switzerland)(IF=3.1). 2020. PMID:32903938. DOI: 10.1159/000507117.
  • [5] Seyyedeh Mina Hejazian;Mohammadreza Ardalan;Seyed Mahdi Hosseiniyan Khatibi;Yalda Rahbar Saadat;Abolfazl Barzegari;Virginie Gueguen;Anne Meddahi-Pellé;Fani Anagnostou;Sepideh Zununi Vahed;Graciela Pavon-Djavid. Biofactors regulating mitochondrial function and dynamics in podocytes and podocytopathies.. Journal of cellular physiology(IF=4.0). 2023. PMID:37659096. DOI: 10.1002/jcp.31110.
  • [6] Yu Sun;Sijia Cui;Yunfeng Hou;Fan Yi. The Updates of Podocyte Lipid Metabolism in Proteinuric Kidney Disease.. Kidney diseases (Basel, Switzerland)(IF=3.1). 2021. PMID:34901191. DOI: 10.1159/000518132.
  • [7] Yusuke Nishimura. Podocytes in health and disease: from development to regeneration.. Human cell(IF=3.1). 2025. PMID:41037130. DOI: 10.1007/s13577-025-01296-7.
  • [8] Klaudia Grochowalska;Piotr Pikul;Agnieszka Piwkowska. Insights into the regulation of podocyte and glomerular function by lactate and its metabolic sensor G-protein-coupled receptor 81.. Journal of cellular physiology(IF=4.0). 2022. PMID:36084306. DOI: 10.1002/jcp.30874.
  • [9] Erina Sugita;Kaori Hayashi;Akihito Hishikawa;Hiroshi Itoh. Epigenetic Alterations in Podocytes in Diabetic Nephropathy.. Frontiers in pharmacology(IF=4.8). 2021. PMID:34630127. DOI: 10.3389/fphar.2021.759299.
  • [10] Irena Audzeyenka;Agnieszka Bierżyńska;Abigail C Lay. Podocyte Bioenergetics in the Development of Diabetic Nephropathy: The Role of Mitochondria.. Endocrinology(IF=3.3). 2022. PMID:34791124. DOI: 10.1210/endocr/bqab234.
  • [11] Siming Yu;Zehui Han;Chunsheng Li;Xinxin Lu;Yue Li;Xingxing Yuan;Dandan Guo. Cross Talk Between Macrophages and Podocytes in Diabetic Nephropathy: Potential Mechanisms and Novel Therapeutics.. Mediators of inflammation(IF=4.2). 2025. PMID:40352596. DOI: 10.1155/mi/8140479.
  • [12] Yuting Li;Jiaojiao Fan;Wenping Zhu;Yujia Niu;Mengqiu Wu;Aihua Zhang. Therapeutic Potential Targeting Podocyte Mitochondrial Dysfunction in Focal Segmental Glomerulosclerosis.. Kidney diseases (Basel, Switzerland)(IF=3.1). 2023. PMID:37900001. DOI: 10.1159/000530344.
  • [13] Di Feng;Clark DuMontier;Martin R Pollak. Mechanical challenges and cytoskeletal impairments in focal segmental glomerulosclerosis.. American journal of physiology. Renal physiology(IF=3.4). 2018. PMID:29363327. DOI: 10.1152/ajprenal.00641.2017.
  • [14] Agnes B Fogo. Causes and pathogenesis of focal segmental glomerulosclerosis.. Nature reviews. Nephrology(IF=39.8). 2015. PMID:25447132. DOI: 10.1038/nrneph.2014.216.
  • [15] Kirk N Campbell;James A Tumlin. Protecting Podocytes: A Key Target for Therapy of Focal Segmental Glomerulosclerosis.. American journal of nephrology(IF=3.2). 2018. PMID:29852493. DOI: 10.1159/000481634.
  • [16] Yu-Ting Zhu;Cheng Wan;Ji-Hong Lin;Hans-Peter Hammes;Chun Zhang. Mitochondrial Oxidative Stress and Cell Death in Podocytopathies.. Biomolecules(IF=4.8). 2022. PMID:35327595. DOI: 10.3390/biom12030403.
  • [17] Jeffrey B Kopp;Hans-Joachim Anders;Katalin Susztak;Manuel A Podestà;Giuseppe Remuzzi;Friedhelm Hildebrandt;Paola Romagnani. Podocytopathies.. Nature reviews. Disease primers(IF=60.6). 2020. PMID:32792490. DOI: 10.1038/s41572-020-0196-7.
  • [18] Linda Reinhard;Rolf A K Stahl;Elion Hoxha. Is primary membranous nephropathy a complement mediated disease?. Molecular immunology(IF=3.0). 2020. PMID:33142137. DOI: 10.1016/j.molimm.2020.10.017.
  • [19] R C Wiggins. The spectrum of podocytopathies: a unifying view of glomerular diseases.. Kidney international(IF=12.6). 2007. PMID:17410103. DOI: 10.1038/sj.ki.5002222.
  • [20] Daria V Ilatovskaya;Alexander Staruschenko. TRPC6 channel as an emerging determinant of the podocyte injury susceptibility in kidney diseases.. American journal of physiology. Renal physiology(IF=3.4). 2015. PMID:26084930. DOI: 10.1152/ajprenal.00186.2015.
  • [21] Ran Nakamichi;Kaori Hayashi;Hiroshi Itoh. Effects of High Glucose and Lipotoxicity on Diabetic Podocytes.. Nutrients(IF=5.0). 2021. PMID:33467659. DOI: 10.3390/nu13010241.
  • [22] Hong Jiang;Zhirang Shen;Jing Zhuang;Chen Lu;Yue Qu;Chengren Xu;Shufen Yang;Xuefei Tian. Understanding the podocyte immune responses in proteinuric kidney diseases: from pathogenesis to therapy.. Frontiers in immunology(IF=5.9). 2023. PMID:38288116. DOI: 10.3389/fimmu.2023.1335936.
  • [23] Stuart J Shankland;Andrew D Rule;J Nathan Kutz;Jeffrey W Pippin;Oliver Wessely. Podocyte Senescence and Aging.. Kidney360(IF=3.0). 2023. PMID:37950369. DOI: 10.34067/KID.0000000000000284.
  • [24] Kristin Meliambro;John C He;Kirk N Campbell. Podocyte-targeted therapies - progress and future directions.. Nature reviews. Nephrology(IF=39.8). 2024. PMID:38724717. DOI: 10.1038/s41581-024-00843-z.
  • [25] Haoyu Yang;Jun Sun;Aru Sun;Yu Wei;Weinan Xie;Pengfei Xie;Lili Zhang;Linhua Zhao;Yishan Huang. Podocyte programmed cell death in diabetic kidney disease: Molecular mechanisms and therapeutic prospects.. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie(IF=7.5). 2024. PMID:39018872. DOI: 10.1016/j.biopha.2024.117140.
  • [26] Sandeep K Mallipattu;John C He. The podocyte as a direct target for treatment of glomerular disease?. American journal of physiology. Renal physiology(IF=3.4). 2016. PMID:27097894. DOI: 10.1152/ajprenal.00184.2016.
  • [27] Jochen Reiser;Vineet Gupta;Andreas D Kistler. Toward the development of podocyte-specific drugs.. Kidney international(IF=12.6). 2010. PMID:20130528. DOI: 10.1038/ki.2009.559.
  • [28] Xuefei Tian;Shuta Ishibe. Targeting the podocyte cytoskeleton: from pathogenesis to therapy in proteinuric kidney disease.. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association(IF=5.6). 2016. PMID:26968197. DOI: 10.1093/ndt/gfw021.
  • [29] Chaojie Zhang;Jia Guo. Cell cycle disorders in podocytes: an emerging and increasingly recognized phenomenon.. Cell death discovery(IF=7.0). 2025. PMID:40246828. DOI: 10.1038/s41420-025-02486-w.
  • [30] Manizheh Khalilpourfarshbafi;Fatemeh Hajiaghaalipour;Kesavanarayanan Krishnan Selvarajan;Aishah Adam. Mesenchymal Stem Cell-Based Therapies against Podocyte Damage in Diabetic Nephropathy.. Tissue engineering and regenerative medicine(IF=4.1). 2017. PMID:30603477. DOI: 10.1007/s13770-017-0026-5.
  • [31] Peter W Mathieson. The podocyte as a target for therapies--new and old.. Nature reviews. Nephrology(IF=39.8). 2011. PMID:22045242. DOI: 10.1038/nrneph.2011.171.
  • [32] Tongcheng Qian;Shaenah E Hernday;Xiaoping Bao;William R Olson;Sarah E Panzer;Eric V Shusta;Sean P Palecek. Directed Differentiation of Human Pluripotent Stem Cells to Podocytes under Defined Conditions.. Scientific reports(IF=3.9). 2019. PMID:30808965. DOI: 10.1038/s41598-019-39504-8.
  • [33] Mark A Lal;Jaakko Patrakka. Understanding Podocyte Biology to Develop Novel Kidney Therapeutics.. Frontiers in endocrinology(IF=4.6). 2018. PMID:30083135. DOI: 10.3389/fendo.2018.00409.
  • [34] Riccardo Bruni;Paolo Possenti;Carlotta Bordignon;Min Li;Stefania Ordanini;Piergiorgio Messa;Maria Pia Rastaldi;Francesco Cellesi. Ultrasmall polymeric nanocarriers for drug delivery to podocytes in kidney glomerulus.. Journal of controlled release : official journal of the Controlled Release Society(IF=11.5). 2017. PMID:28395969. DOI: 10.1016/j.jconrel.2017.04.005.

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