Angiotensin system modulation in focal segmental glomerulosclerosis: pharmacological basis and clinical implications

INTRODUCTION: FSGS is a histological convergence point for biologically distinct conditions: primary immune-mediated, genetic, and secondary adaptive forms, each with its own pharmacological logic. ACE inhibitors and angiotensin receptor blockers have anchored its management for three decades on evidence drawn predominantly from non-FSGS populations. AREAS COVERED: Experimental and clinical literature from PubMed/MEDLINE, Embase, and Web of Science through 30 January 2026, covering angiotensin II-mediated podocyte injury, RAAS pharmacology across FSGS subtypes, and emerging strategies that extend or layer upon the RAAS backbone, including dual AT1/endothelin-A blockade, SGLT2 inhibition, and mineralocorticoid receptor antagonism, with additional podocyte-targeted and genotype-guided approaches. EXPERT OPINION: The clinical benefit of RAAS blockade appears to vary across FSGS subtypes. It likely targets a key pathogenic mechanism in secondary adaptive forms, while serving mainly as supportive antiproteinuric therapy in immune-mediated and genetic disease. Nonetheless, it remains a cornerstone of care.Emerging therapies, including dual AT1/endothelin-A antagonism (sparsentan) and podocyte-targeted approaches (apecotrep), show promising proteinuria reductions but have not yet demonstrated clear benefits on hard renal outcomes. Biomarker-driven strategies (e.g. anti-nephrin antibodies, APOL1 genotyping) may enable more tailored treatment, although their clinical impact remains to be established.