The Gamma Subunit of the Epithelial Sodium Channel (gENaC) in Vascular Smooth Muscle Mediates Glomerular Filtration Rate (GFR) with Angiotensin II

The epithelial sodium channel (ENaC) within smooth muscle cells has been shown to play a role in mediating myogenic tone of blood vessels. Previous studies found that mice with whole body knockdown of the beta subunit of ENaC experienced a loss of myogenic tone in the renal vasculature which caused renal injury, inflammation, and glomerular damage which eventually led to increased blood pressure. However, as these results were obtained in an animal with global suppression of beta ENaC expression, the contributions of vascular smooth muscle (VSM) ENaC cannot be separated from the effects of ENaC expression within other sites such as the endothelium, renal tubule, and immune cells. To address this concern, we generated a VSM gamma ENaC knockout mouse using cre-lox technology. Using radiotelemetry, we found no significant difference in baseline blood pressure in these animals compared to littermate controls. To observe if renal injury occurred in the mice under stressed conditions, a unilateral nephrectomy was performed on mice between 11-16 weeks of age and angiotensin II (AngII) was administered for four weeks (1.5mg/kg/day) via minipump. Glomerular filtration rate was assessed with a transdermal probe that measures circulating FITC-sinistrin following retro-orbital delivery of a bolus injection. Loss of gamma ENaC resulted in a decreased FITC-sinistrin half-life (higher GFR) over the four weeks of AngII treatment as compared to control mice in males, but a significant difference was not detected in females. Urinary albumin excretion, assessed over 24 hours via metabolic cage collections, revealed no differences between knockout animals and controls in males or females. Assessment of mRNA levels for renal tubule injury markers KIM1 and NGAL by qPCR also revealed no significant differences between control and knockout mice at the end of the four-week AngII treatment. Together, these data suggest that while vascular smooth muscle gamma ENaC may mediate GFR with AngII administration in male mice, this loss of myogenic response does not lead to more severe renal injury. However, future studies will assess histology and markers of glomerular injury to further phenotype the model. This study was funded by National Institutes of Health grants: R01 DK111380, R01 DK137167, R01 DK130901, and U54 DK137329. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.