Faculty Opinions recommendation of Synaptopodin deficiency exacerbates kidney disease in a mouse model of Alport Syndrome.

Synaptopodin (Synpo) is an actin-associated protein in podocyte foot processes. By generating mice that completely lack Synpo, we previously showed that Synpo is dispensable for normal kidney function. However, the lack of Synpo worsened Adriamycin nephropathy, indicating a protective role for Synpo in injured podocytes. Here we investigated whether the lack of Synpo directly impacts a genetic disease, Alport syndrome (AS), because Synpo is reduced in the podocytes of affected humans and mice; whether this is merely an association or pathogenic is unknown. We used Col4a5 mutant mice that model X-linked AS, showing glomerular basement membrane (GBM) abnormalities, eventual foot process effacement, and progression to ESKD. We intercrossed mice carrying mutations in Synpo and Col4a5 to produce doubly mutant mice. Urine and tissue were taken at select time points to evaluate albuminuria, histopathology, and glomerular capillary wall composition and ultrastructure. The lack of Synpo in Col4a5-/Y, Col4a5-/-, or Col4a5+/- Alport mice led to acceleration of disease progression, including more severe proteinuria and glomerulosclerosis. The absence of Synpo attenuated the shift of myosin IIA from the podocyte cell body and major processes to the actin cables near the GBM in the areas of effacement. We speculate that this is mechanistically associated with enhanced loss of podocytes due to easier detachment from the GBM. We conclude that Synpo deletion exacerbates the disease phenotype in Alport mice, revealing the podocyte actin cytoskeleton as a target for therapy in patients with AS. PMID: 34029143 Funding information This work was supported by: American Heart Association (AHA), Grant ID: 17SDG33420069 HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Grant ID: P30DK020579 HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Grant ID: R01DK078314 HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Grant ID: R01DK058366