Novel Mechanism for Tubular Injury in Nephropathic Cystinosis

• DOI: 10.7554/elife.94169.2
• Publication Date: 2025-01-31T18:25:46Z
• Authors: Swastika Sur; Maggie Kerwin; Silvia Pineda; Poonam Sansanwal; Tara K Sigdel; Marina Sirota; Minnie M Sarwal
• Keywords: Cystinosis; Autophagosome

Understanding the unique susceptibility of human kidney to pH dysfunction and injury in cystinosis is paramount developing new therapies preserve renal function. Renal proximal tubular epithelial cells (RPTECs) fibroblasts isolated from patients with were transcriptionally profiled. Lysosomal fractionation, immunoblotting, confocal microscopy, intracellular pH, TEM, mitochondrial stress test, membrane integrity assays performed for validation. CRISPR, CTNS -/- RPTECs generated. Alterations cell stress, autophagic turnover, energetics highlighted key changes vacuolar (V)-ATPases patient-derived RPTECs. ATP6V0A1 was significantly downregulated highly co-regulated loss . Correction rescued Treatment antioxidants astaxanthin (ATX) induced expression improved autophagosome turnover integrity.In conclusion, our exploratory transcriptional vitro cellular functional studies confirm that cystinosin RPTECs, results a reduction expression, integrity, function, autophagosome-lysosome clearance. The novel findings are ATP6V0A1’s role cystinosis-associated pathology among other antioxidants, ATX specifically upregulated ATP6V0A1, or reduced autophagy integrity. This pilot study highlighting mechanism requires further animal models clarify its utility clinical settings.