Keywords
Podocytes
Pathogenesis
Proteinuria
Submitted : 2025-06-08
Accepted : 2025-06-23
Published : 2025-07-08
Abstract
Pre-eclampsia is still one of the leading causes of maternal and fetal morbidity and mortality worldwide, affecting multiple organ systems. Despite extensive research, its underlying etiology remains unclear. Proteinuria is a hallmark of a diagnosis of preeclampsia and is usually accompanied by podocyte damage, which is changes in the structure and function of the podocytes. Recent technological advances have identified a critical role for podocytes in the loss of renal filtration function in preeclampsia. However, the molecular mechanisms leading to proteinuria and podocyte damage in preeclampsia are unknown, which leads to a lack of targeted therapy. Recent years have witnessed challenges the traditional view, that kidney damage in preeclampsia is caused only by glomerular endothelial cell injury. Similarly, podocytes were identified as key players in the pathogenesis of proteinuria in preeclampsia. In this review, we review the mechanisms of renal injury (especially podocytes) in preeclampsia to elucidate the relevance of podocyte injury to proteinuria and suggest specific therapeutic strategies for proteinuria in preeclampsia.
References
Tersigni C, Maulucci G, Castellani R, et al., 2022, Enoxaparin Increases D6 Receptor Expression and Restores Cytoskeleton Organization in Trophoblast Cells from Preeclampsia. Cells, 11(13): 2036.
Kornacki J, Olejniczak O, Sibiak R, et al., 2023, Pathophysiology of Pre-Eclampsia—Two Theories of the Development of the Disease. International Journal of Molecular Sciences, 25(1): 307.
Cormick G, Betran A, Ciapponi A, et al., 2016, Inter-Pregnancy Interval and Risk of Recurrent Pre-Eclampsia: Systematic Review and Meta-Analysis. Reproductive Health, 13: 1–10.
Program N, 2000, Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. American Journal of Obstetrics and Gynecology, 183(1): S1–S22.
Assady S, Wanner N, Skorecki K, et al., 2017, New Insights into Podocyte Biology in Glomerular Health and Disease. Journal of the American Society of Nephrology, 28(6): 1707–1715.
Embarazo A, Saleem M, Bueno J, et al., 2007, A Novel Renal Perspective of Preeclampsia: A Look from the Podocyte. Nephrol Dial Transplant, 22(5): 1477–1490.
Liévano S, Alarcón L, Chávez–Munguía B, et al., 2006, Endothelia of Term Human Placentae Display Diminished Expression of Tight Junction Proteins During Preeclampsia. Cell and Tissue Research, 324(3): 433–448.
Sun H, Li H, Yan J, et al., 2022, Loss of CLDN5 in Podocytes Deregulates WIF1 to Activate WNT Signaling and Contributes to Kidney Disease. Nature Communications, 13(1): 1600.
Balkawade R, Chen C, Crowley M, et al., 2019, Podocyte-Specific Expression of Cre Recombinase Promotes Glomerular Basement Membrane Thickening. American Journal of Physiology–Renal Physiology, 316(5): F1026–F1040.
Mo H, Wu Q, Miao J, et al., 2017, CXC Chemokine Receptor Type 4 Plays a Crucial Role in Mediating Oxidative Stress-Induced Podocyte Injury. Antioxidants & Redox Signaling, 27(6): 345–362.
Zheng Z, Chen H, Zhu S, et al., 2021, CXCR4/CXCR7 Protein Expression Levels in Placentas of Patients with Preeclampsia. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research, 27: e931192–1.
Georgopoulos N, Kirkwood L, Southgate J, 2014, A Novel Bidirectional Positive-Feedback Loop Between Wnt–β-Catenin and EGFR–ERK Plays a Role in Context-Specific Modulation of Epithelial Tissue Regeneration. Journal of Cell Science, 127(13): 2967–2982.
MacLaine N, Wood M, Holder J, et al., 2008, Sensitivity of Normal, Paramalignant, and Malignant Human Urothelial Cells to Inhibitors of the Epidermal Growth Factor Receptor Signaling Pathway. Molecular Cancer Research, 6(1): 53–63.
Pawig L, Klasen C, Weber C, et al., 2015, Diversity and Inter-Connections in the CXCR4 Chemokine Receptor/Ligand Family: Molecular Perspectives. Frontiers in Immunology, 6: 156039.
Chen Q, Yin Y, Wei J, et al., 2016, Increased Expression of High Mobility Group Box 1 (HMGB1) in the Cytoplasm of Placental Syncytiotrophoblast from Preeclamptic Placentae. Cytokine, 85: 30–36.
Weel I, Romão-Veiga M, Matias M, et al., 2017, Increased Expression of NLRP3 Inflammasome in Placentas from Pregnant Women with Severe Preeclampsia. Journal of Reproductive Immunology, 123: 40–47.
Sánchez-Aranguren L, Prada C, Riaño-Medina C, et al., 2014, Endothelial Dysfunction and Preeclampsia: Role of Oxidative Stress. Frontiers in Physiology, 5: 99092.
Abais J, Xia M, Li G, et al., 2014, Contribution of Endogenously Produced Reactive Oxygen Species to the Activation of Podocyte NLRP3 Inflammasomes in Hyperhomocysteinemia. Free Radical Biology and Medicine, 67: 211–220.
Yan J, Li Y, Yang H, et al., 2018, Interleukin‐17A Participates in Podocyte Injury by Inducing IL‐1β Secretion Through ROS‐NLRP3 Inflammasome‐Caspase‐1 Pathway. Scandinavian Journal of Immunology, 87(4): e12645.
Chang G, Yang X, Liu W, et al., 2021, RETRACTED: FABP4 Facilitates Inflammasome Activation to Induce the Treg/Th17 Imbalance in Preeclampsia via Forming a Positive Feedback with IL-17A. Molecular Therapy-Nucleic Acids, 24: 743–754.
Schoots M, Gordijn S, Scherjon S, et al., 2018, Oxidative Stress in Placental Pathology. Placenta, 69: 153–161.
Silvestro S, Calcaterra V, Pelizzo G, et al., 2020, Prenatal Hypoxia and Placental Oxidative Stress: Insights from Animal Models to Clinical Evidences. Antioxidants, 9(5): 414.
Myatt L, Cui X, 2004, Oxidative Stress in the Placenta. Histochemistry and Cell Biology, 122: 369–382.
Wen Y, Liu L, Xu Q, et al., 2018, Knocking Down Cabin1 Induces Glomerular Podocyte Injury. International Urology and Nephrology, 50: 983–991.
Circu M, Aw T, 2010, Reactive Oxygen Species, Cellular Redox Systems, and Apoptosis. Free Radical Biology and Medicine, 48(6): 749–762.
Sachse A, Wolf G, 2007, Angiotensin II–Induced Reactive Oxygen Species and the Kidney. Journal of the American Society of Nephrology, 18(9): 2439–2446.
Zhou L, Cao W, Xie C, et al., 2012, The Receptor of Advanced Glycation End Products Plays a Central Role in Advanced Oxidation Protein Products-Induced Podocyte Apoptosis. Kidney International, 82(7): 759–770.
Zhou L, Chen X, Lu M, et al., 2019, Wnt/β-Catenin Links Oxidative Stress to Podocyte Injury and Proteinuria. Kidney International, 95(4): 830–845.
Eremina V, Jefferson J, Kowalewska J, et al., 2008, VEGF Inhibition and Renal Thrombotic Microangiopathy. New England Journal of Medicine, 358(11): 1129–1136.
Harper S, Xing C, Whittle C, et al., 2001, Expression of Neuropilin-1 by Human Glomerular Epithelial Cells In Vitro and In Vivo. Clinical Science, 101(4): 439–446.
Henao D, Cadavid Á, Saleem M, 2013, Exogenous Vascular Endothelial Growth Factor Supplementation Can Restore the Podocyte Barrier‐Forming Capacity Disrupted by Sera of Preeclamptic Women. Journal of Obstetrics and Gynaecology Research, 39(1): 46–52.
Foster R, Hole R, Anderson K, et al., 2003, Functional Evidence That Vascular Endothelial Growth Factor May Act as an Autocrine Factor on Human Podocytes. American Journal of Physiology-Renal Physiology, 284(6): F1263–F1273.
Müller-Deile J, Schenk H, Schiffer M, 2019, Minimal Change Disease and Focal Segmental Glomerulosclerosis. Der Internist, 60: 450–457.
Cruz-Topete D, Cidlowski J, 2014, One Hormone, Two Actions: Anti- and Pro-Inflammatory Effects of Glucocorticoids. Neuroimmunomodulation, 22(1–2): 20–32.
Li X, Chuang P, D’Agati V, et al., 2015, Nephrin Preserves Podocyte Viability and Glomerular Structure and Function in Adult Kidneys. Journal of the American Society of Nephrology, 26(10): 2361–2377.
Broek M, Smeets B, Schreuder M, et al., 2022, The Podocyte as a Direct Target of Glucocorticoids in Nephrotic Syndrome. Nephrology Dialysis Transplantation, 37(10): 1808–1815.
Zhao X, Khurana S, Charkraborty S, et al., 2017, α Actinin 4 (ACTN4) Regulates Glucocorticoid Receptor-Mediated Transactivation and Transrepression in Podocytes. Journal of Biological Chemistry, 292(5): 1637–1647.
Agrawal S, Chanley M, Westbrook D, et al., 2016, Pioglitazone Enhances the Beneficial Effects of Glucocorticoids in Experimental Nephrotic Syndrome. Scientific Reports, 6(1): 24392.
Liu J, Gao X, Zhai Y, et al., 2015, A Novel Role of Angiopoietin-Like-3 Associated with Podocyte Injury. Pediatric Research, 77(6): 732–739.
Lv Q, Han X, Ni J, et al., 2022, Anti-ANGPTL3-FLD Monoclonal Antibody Treatment Ameliorates Podocyte Lesions Through Attenuating Mitochondrial Damage. Cell Death & Disease, 13(10): 867.
Hackl A, Nüsken E, Voggel J, et al., 2023, The Effect of Mycophenolate Mofetil on Podocytes in Nephrotoxic Serum Nephritis. Scientific Reports, 13(1): 14167.