Functional coupling of cellular metabolism and renal hemodynamics underlies kidney sex differences

Age-related renal function decline is faster in males than in age-matched females, manifesting in increased susceptibility to both chronic and acute kidney diseases among males, in humans and rodents. Single-cell analysis on the mouse kidney demonstrated that sexually dimorphic gene activity maps predominantly to proximal tubule (PT) segments, where male-biased lipid metabolism implies exacerbated energy demands for reabsorption. Using intravital microscopy on mouse kidneys, we captured spontaneous metabolic oscillations in individual PT cells and real-time single-nephron glomerular filtration rate (GFR) oscillations, revealing functional coupling between cell-level metabolism and tissue-level fluid flow in vivo. GFR is tightly regulated by tubuloglomerular feedback (TGF) within renal tubules to optimize filtration of plasma and reabsorption of essential molecules. We found that TGF-mediated GFR oscillations also show sex-biased characteristics, with males exhibiting higher frequencies. Mathematical modeling of TGF indicates that differential metabolic states in renal tubules can account for sex differences in GFR dynamics. Male kidneys are more prone to loss of TGF-mediated autoregulation, thus explaining sexual dimorphism in renal aging and diseases. Supported by NIH grant R01-AI17321 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.