What question did this study set out to answer?

This study aims to understand molecular mechanisms driving podocyte dysfunction and evaluate the impact of specific gene knockouts on kidney health.

March 28, 2026Kidney International Reports0 citationsOpen Access

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PMPriti Meena DPDr Prof S. S. Panda PDParomita Das

Key Points

This study aims to understand molecular mechanisms driving podocyte dysfunction and evaluate the impact of specific gene knockouts on kidney health.
Utilized Tln1-cKO mice to model impaired focal adhesion
Conducted single-cell RNA sequencing for molecular changes
Generated Nsf-cKO mice for targeted gene studies
Performed assays to assess cell spreading and podocyte morphology
Applied live-cell imaging via RUSH system
Identified Nsf as significantly downregulated in injured podocytes
Nsf deletion led to severe proteinuria and increased podocyte loss
Observed glomerulosclerosis and renal failure in Nsf-cKO mice
Early mortality was noted by 3 weeks in the Nsf-cKO cohort

Abstract

Introduction:The adhesion of podocytes-terminally differentiated epithelial cells-to the glomerular basement membrane is critical for kidney function.While adhesion disruption causes podocyte loss, the molecular mechanisms by which impaired focal adhesion drives progressive podocyte dysfunction and cell loss in glomerulosclerosis remain poorly understood.Methods: We used doxycycline-inducible podocyte-specific Tln1 knockout (Tln1-cKO) mice, an established model of impaired focal adhesion, and performed single-cell RNA sequencing to identify early molecular changes.To investigate a key candidate gene, we generated podocyte-specific Nsf knockout (Nsf-cKO) mice and assessed them using cell spreading assays, morphological and molecular analyses, and live-cell imaging using the Retention Using Selective Hooks (RUSH) system.Results: Screening of Tln1-cKO podocytes revealed Nsf, which encodes N-ethylmaleimide-sensitive factor (NSF)-an AAA+ ATPase essential for vesicular trafficking by disassembling soluble NSF attachment protein receptor complexes-as one of the most significantly downregulated genes in injured podocytes.Podocyte-specific Nsf deletion resulted in massive proteinuria, podocyte loss, glomerulosclerosis, tubulointerstitial fibrosis, renal failure, and early mortality by 3 weeks.Nsf-cKO podocytes exhibited impaired cell spreading, with defective

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