Podocyte Damage Molecular Mechanisms Preeclampsia 2023 Review

Preeclampsia, a pregnancy-specific hypertensive disorder, remains a leading cause of maternal and perinatal morbidity and mortality worldwide. At the heart of this complex syndrome lies widespread endothelial dysfunction and a characteristic renal involvement, with proteinuria serving as a key diagnostic criterion. Podocyte damage, increasingly recognized as a critical factor in preeclampsia, contributes significantly to the development of proteinuria and the overall pathogenesis of the disease. This review aims to delve into the molecular mechanisms underlying podocyte damage in preeclampsia, providing an updated perspective for 2023.

Understanding Preeclampsia and its Renal Manifestations

Preeclampsia is defined by new-onset hypertension and proteinuria, or new-onset hypertension with significant end-organ dysfunction, typically occurring after 20 weeks of gestation. The pathogenesis of preeclampsia is multifactorial, involving abnormal placentation, endothelial dysfunction, systemic inflammation, and an imbalance in angiogenic factors.

The kidney, in particular the glomerulus, is a major target in preeclampsia. Glomerular endotheliosis, characterized by swelling of endothelial cells lining the glomerular capillaries, is a hallmark pathological finding. This leads to a reduction in glomerular filtration surface area and subsequent proteinuria. Podocyte damage, often accompanying endotheliosis, further exacerbates the glomerular dysfunction.

The Vital Role of Podocytes

Podocytes are highly specialized, terminally differentiated cells that reside in the visceral layer of Bowman's capsule in the kidney glomerulus. These cells play a crucial role in maintaining the glomerular filtration barrier (GFB), which selectively filters blood to produce urine while preventing the passage of large proteins, such as albumin, into the filtrate.

• Structure: Podocytes possess a unique structure characterized by a cell body, major processes, and numerous interdigitating foot processes that wrap around the glomerular capillaries. These foot processes are connected by a specialized cell-cell junction called the slit diaphragm.
• Function: The slit diaphragm, along with the glomerular basement membrane (GBM) and the endothelial glycocalyx, forms the GFB. Podocytes contribute to the GFB by:
  • Providing a size-selective barrier through the slit diaphragm.
  • Synthesizing and maintaining the GBM.
  • Regulating glomerular capillary permeability.
• Vulnerability: Due to their unique structure, limited regenerative capacity, and critical function, podocytes are highly vulnerable to injury. Podocyte damage, characterized by foot process effacement (flattening), detachment from the GBM, and ultimately podocyte loss, leads to disruption of the GFB and proteinuria.

Molecular Mechanisms of Podocyte Damage in Preeclampsia

The molecular mechanisms driving podocyte damage in preeclampsia are complex and involve a multitude of factors, including placental factors, immune dysregulation, and direct effects of hypertension.

1. Placental Factors and Anti-angiogenic Imbalance

A central feature of preeclampsia is abnormal placentation, leading to placental ischemia and the release of various factors into the maternal circulation. These factors, particularly anti-angiogenic proteins, play a significant role in causing endothelial dysfunction and podocyte damage.

• Soluble fms-like tyrosine kinase 1 (sFlt-1): sFlt-1 is a soluble form of the vascular endothelial growth factor receptor 1 (VEGFR-1). In preeclampsia, the placenta overproduces sFlt-1, which binds to and neutralizes VEGF and placental growth factor (PlGF), key angiogenic factors essential for endothelial cell survival and function.
  • Mechanism of Podocyte Damage: sFlt-1-mediated reduction in VEGF and PlGF disrupts podocyte signaling pathways crucial for maintaining their structure and function. VEGF is known to promote podocyte survival, proliferation, and differentiation. Its inhibition by sFlt-1 leads to:
    • Disruption of the actin cytoskeleton: VEGF signaling is critical for maintaining the actin cytoskeleton, which is essential for foot process structure and dynamics. sFlt-1-induced VEGF inhibition causes actin stress fiber formation, foot process effacement, and impaired cell motility.
    • Decreased expression of slit diaphragm proteins: VEGF regulates the expression of key slit diaphragm proteins, such as nephrin and podocin. sFlt-1 reduces their expression, leading to slit diaphragm dysfunction and increased permeability.
    • Increased podocyte apoptosis: VEGF acts as a survival factor for podocytes. sFlt-1-mediated VEGF inhibition triggers apoptosis pathways, leading to podocyte loss.
• Soluble Endoglin (sEng): sEng is a soluble form of endoglin, a co-receptor for transforming growth factor-beta (TGF-β). sEng is also overexpressed in preeclampsia and contributes to endothelial dysfunction.
  • Mechanism of Podocyte Damage: sEng binds to TGF-β, preventing it from signaling through its receptors. TGF-β plays a complex role in the kidney, but it is generally considered to be protective for podocytes by promoting their differentiation and survival. sEng-mediated inhibition of TGF-β signaling leads to:
    • Increased oxidative stress: sEng promotes the production of reactive oxygen species (ROS) in podocytes, leading to oxidative damage to cellular components.
    • Enhanced inflammatory responses: sEng activates inflammatory pathways in podocytes, contributing to cellular injury and dysfunction.
    • Dysregulation of podocyte matrix interactions: TGF-β is involved in regulating the interaction between podocytes and the GBM. sEng-mediated inhibition disrupts this interaction, leading to podocyte detachment.

2. Immune Dysregulation and Inflammatory Mediators

Preeclampsia is associated with systemic inflammation and immune dysregulation. An imbalance in immune cell populations and increased production of pro-inflammatory cytokines contribute to endothelial dysfunction and podocyte damage.

• T cells and Cytokines: An abnormal activation of T cells, particularly Th1 and Th17 cells, is observed in preeclampsia. These cells release pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-17 (IL-17).
  • Mechanism of Podocyte Damage: These cytokines directly or indirectly contribute to podocyte damage through:
    • Direct cytotoxicity: TNF-α can directly induce podocyte apoptosis through activation of caspase pathways.
    • Increased oxidative stress: Pro-inflammatory cytokines promote the production of ROS in podocytes, leading to oxidative damage.
    • Disruption of the actin cytoskeleton: IL-6 and IL-17 can alter the expression and localization of actin-binding proteins, leading to foot process effacement.
    • Increased glomerular permeability: Cytokines can directly increase the permeability of the GFB by disrupting the slit diaphragm and altering the expression of tight junction proteins.
• Complement Activation: The complement system, a crucial part of the innate immune system, is abnormally activated in preeclampsia. This activation leads to the production of complement components, such as C5a and the membrane attack complex (MAC), which can damage endothelial cells and podocytes.
  • Mechanism of Podocyte Damage: Complement activation contributes to podocyte damage through:
    • Direct lysis: The MAC can directly lyse podocytes, leading to cell death and loss of glomerular integrity.
    • Inflammation: C5a is a potent chemoattractant for immune cells and promotes the release of pro-inflammatory cytokines, further exacerbating podocyte injury.
    • Sublytic MAC formation: Even in the absence of direct lysis, sublytic MAC formation can alter podocyte function by disrupting calcium homeostasis and promoting the release of ROS.

3. Direct Effects of Hypertension and Hemodynamic Stress

Hypertension is a defining feature of preeclampsia, and the elevated blood pressure can directly impact podocytes. The increased hemodynamic stress on the glomerulus can lead to podocyte injury and detachment.

• Mechanical Stress: The increased pressure within the glomerular capillaries exerts mechanical stress on podocytes, particularly on their foot processes. This stress can disrupt the actin cytoskeleton, leading to foot process effacement and detachment.
  • Mechanism of Podocyte Damage:
    • Actin cytoskeleton disruption: Mechanical stress can activate signaling pathways that alter the expression and localization of actin-binding proteins, leading to foot process effacement.
    • Focal adhesion kinase (FAK) activation: Mechanical stress activates FAK, a key regulator of cell adhesion and migration. FAK activation can lead to podocyte detachment from the GBM.
    • Increased permeability: Mechanical stress can directly increase the permeability of the GFB by disrupting the slit diaphragm and altering the expression of tight junction proteins.
• Glomerular Hyperfiltration: In some cases of preeclampsia, there may be an initial phase of glomerular hyperfiltration before the development of overt renal dysfunction. This hyperfiltration can also contribute to podocyte damage by increasing the workload on these cells.
  • Mechanism of Podocyte Damage:
    • Increased protein traffic: Hyperfiltration increases the amount of protein that podocytes must process, leading to endoplasmic reticulum (ER) stress and cellular dysfunction.
    • Activation of profibrotic pathways: Hyperfiltration can activate profibrotic pathways in podocytes, leading to extracellular matrix accumulation and glomerular sclerosis.

4. Endoplasmic Reticulum (ER) Stress and Unfolded Protein Response (UPR)

ER stress occurs when the ER, a cellular organelle responsible for protein folding and processing, is overwhelmed by an accumulation of misfolded or unfolded proteins. This can be triggered by various factors, including oxidative stress, inflammation, and increased protein traffic. The UPR is a cellular response to ER stress, aimed at restoring ER homeostasis. However, prolonged or excessive ER stress can lead to cell death.

• Mechanism of Podocyte Damage:
  • Activation of apoptotic pathways: Prolonged ER stress activates apoptotic pathways, leading to podocyte death.
  • Disruption of cellular function: ER stress can disrupt various cellular functions, including protein synthesis, calcium homeostasis, and lipid metabolism, leading to podocyte dysfunction.
  • Inflammation: ER stress can activate inflammatory pathways, further exacerbating podocyte injury.
• Factors contributing to ER stress in preeclampsia:
  • Increased protein traffic due to hyperfiltration.
  • Oxidative stress induced by sEng and pro-inflammatory cytokines.
  • Disruption of calcium homeostasis by complement activation.

5. Genetic Predisposition and Individual Susceptibility

Genetic factors play a role in the susceptibility to preeclampsia. Certain genetic variants may increase the risk of developing preeclampsia and experiencing podocyte damage.

• Polymorphisms in genes encoding slit diaphragm proteins: Variations in genes encoding nephrin, podocin, and other slit diaphragm proteins can affect the integrity of the GFB and increase susceptibility to podocyte damage.
• Polymorphisms in genes involved in VEGF signaling: Variations in genes encoding VEGF, VEGFR-1, and other components of the VEGF signaling pathway can affect podocyte survival and function.
• Polymorphisms in genes involved in immune regulation: Variations in genes encoding cytokines, complement components, and other immune regulators can affect the inflammatory response and contribute to podocyte damage.
• Epigenetic modifications: Epigenetic modifications, such as DNA methylation and histone modification, can also influence gene expression and contribute to individual susceptibility to preeclampsia and podocyte damage.

Therapeutic Strategies Targeting Podocyte Damage in Preeclampsia

Given the critical role of podocyte damage in the pathogenesis of preeclampsia, therapeutic strategies aimed at protecting podocytes are of great interest.

• Anti-angiogenic therapies:
  • sFlt-1 inhibitors: Developing sFlt-1 inhibitors to restore VEGF and PlGF levels could protect podocytes from damage.
  • VEGF supplementation: Administration of VEGF may promote podocyte survival and function.
• Anti-inflammatory therapies:
  • TNF-α inhibitors: Blocking TNF-α could reduce podocyte apoptosis and inflammation.
  • Complement inhibitors: Inhibiting complement activation may prevent podocyte lysis and inflammation.
• Antioxidant therapies:
  • Administering antioxidants: Could reduce oxidative stress and protect podocytes from damage.
• Targeting ER stress:
  • Chemical chaperones: Could help to reduce ER stress and promote protein folding.
• Glomerular protection:
  • RAS inhibitors: While contraindicated in pregnancy, research into safe alternatives could provide glomerular protection and reduce damage progression.

Future Directions and Research Priorities

Further research is needed to fully elucidate the molecular mechanisms underlying podocyte damage in preeclampsia and to develop effective therapeutic strategies. Some key areas for future research include:

• Identifying novel biomarkers: Identifying novel biomarkers that can detect early podocyte damage in preeclampsia would allow for earlier intervention and potentially prevent disease progression.
• Developing podocyte-specific therapies: Developing therapies that specifically target podocytes would minimize off-target effects and maximize therapeutic efficacy.
• Investigating the role of genetic factors: Further investigating the role of genetic factors in preeclampsia susceptibility and podocyte damage would allow for personalized risk assessment and targeted interventions.
• Studying the long-term consequences of podocyte damage: Studying the long-term consequences of podocyte damage in preeclampsia would help to understand the increased risk of chronic kidney disease in women who have experienced preeclampsia.

Conclusion

Podocyte damage is a critical component of the pathophysiology of preeclampsia, contributing significantly to proteinuria and overall disease severity. The molecular mechanisms underlying podocyte damage are complex and involve placental factors, immune dysregulation, hemodynamic stress, and genetic predisposition. Understanding these mechanisms is essential for developing effective therapeutic strategies to protect podocytes and improve outcomes for women with preeclampsia. Future research should focus on identifying novel biomarkers, developing podocyte-specific therapies, and investigating the long-term consequences of podocyte damage in preeclampsia. As research continues to unfold, the insights gained will undoubtedly pave the way for more targeted and effective interventions, ultimately leading to improved maternal and fetal outcomes in this challenging pregnancy complication.