Emerging Targets in Podocyte Injury Signal Shift in Glomerular Disease Treatment, With John Cijiang He, MD, PhD

An evolving understanding of podocyte injury in glomerular disease is being driven by advances in genetics, targeted therapeutics, and biomarker development, signaling a shift beyond traditional immunosuppression.

Recently, John Cijiang He, MD, PhD, Professor of Medicine and Pharmacological Sciences and Chief of the Division of Nephrology at the Icahn School of Medicine at Mount Sinai, spoke with HCPLive at the World Congress of Nephrology (WCN). In Part 1, he discussed the growing recognition of podocyte injury as a central mechanism in focal segmental glomerulosclerosis (FSGS) and diabetic kidney disease.

Podocytes are highly specialized visceral epithelial cells that, along with glomerular endothelial cells and the glomerular basement membrane, form the glomerular filtration barrier. This structure allows waste products to pass while preventing the leakage of plasma proteins such as albumin. Podocytes are characterized by interdigitating foot processes connected by slit diaphragms, which serve as a critical final filtration barrier.

A notable feature of podocytes is that they are terminally differentiated, meaning they have limited capacity to proliferate. As a result, podocyte loss is difficult to recover. Injury caused by infection, genetic defects, or immune-mediated damage can lead to foot process effacement, disruption of the slit diaphragm, and proteinuria, currently the most widely used noninvasive biomarker of glomerular injury. Progressive podocyte damage contributes to chronic kidney disease (CKD) and eventual kidney failure.

Genetic mutations remain a key driver of podocyte injury, particularly in pediatric populations. In addition, APOL1 high-risk variants, most commonly identified in individuals of African ancestry, are strongly associated with increased risk of kidney disease. APOL1-mediated glomerular disease often presents similarly to FSGS and is thought to involve mechanisms including dysregulated ion channel activity that contribute to podocyte injury.

Proteinuria, while widely used in clinical practice, may reflect relatively advanced disease, with substantial podocyte injury already present at the time of detection. As a result, emerging therapeutic strategies are being explored, including early-stage gene-based approaches and interventions targeting downstream molecular pathways to restore podocyte function. These approaches align with a broader shift toward precision medicine in nephrology.

In APOL1-associated disease, early-phase clinical trials have demonstrated reductions in proteinuria with small molecule inhibitors targeting APOL1-mediated pathways. Ongoing phase 3 trials are further evaluating these therapies, which could represent the first targeted treatment for a genetically defined subgroup of glomerular disease.

Additional emerging targets include lipid toxicity and metabolic dysfunction. Dysregulated lipid uptake in podocytes can lead to lipotoxicity and cellular injury, prompting investigation into therapies that inhibit lipid accumulation. Furthermore, ion channel dysregulation, such as gain-of-function mutations, has been implicated in podocyte injury. Targeted inhibitors of these pathways are currently being evaluated in phase 2 clinical trials, with early data suggesting potential reductions in proteinuria.

Although these approaches remain investigational, they underscore a growing shift toward mechanism-based, podocyte-directed therapies in glomerular disease.

References

1. Reiser J, Altintas MM. Podocytes. F1000Research. 2016;5(1):114. doi:https://doi.org/10.12688/f1000research.7255.1

2. Hillenbrand A. Podocyte Injury Emerges as Central Driver of Progression in FSGS, Diabetic Kidney Disease. HCPLive. Published 2026. Accessed April 7, 2026. https://www.hcplive.com/view/podocyte-injury-emerges-as-central-driver-of-progression-in-fsgs-and-diabetic-kidney-disease

3. Zimmerman B, Dakin LA, Fortier A, et al. Small molecule APOL1 inhibitors as a precision medicine approach for APOL1-mediated kidney disease. Nature Communications. 2025;16(1). doi:https://doi.org/10.1038/s41467-024-55408-2

4. Luo Z, Chen Z, Hu J, Ding G. Interplay of lipid metabolism and inflammation in podocyte injury. Metabolism: clinical and experimental. 2024;150:155718. doi:https://doi.org/10.1016/j.metabol.2023.155718

5. Hu H, Liang W, Ding G. Podocyte Metabolic Reprogramming and Targeted Therapy. Journal of the American Society of Nephrology : JASN. 2026;37(3):619-633. doi:https://doi.org/10.1681/ASN.0000000917