LAUSR

Evidence suggests that decline in renal function is more severe in males than in age-matched females, manifesting in increased susceptibility to both chronic and acute kidney diseases among males. Our previous single-cell studies on renal transcriptomes in human and mouse demonstrated that sex differences are the most prominent in proximal tubules (PTs), where over 70% of salt reabsorption happens. However, it remains elusive how these molecular differences affect renal physiology and pathophysiology. Widely known as an indicator of renal function, glomerular filtration rate (GFR) is tightly regulated by tubuloglomerular feedback (TGF) within the nephron to optimize ultrafiltration of plasma and reabsorption of essential molecules. Importantly, GFR shows a sustained oscillatory pattern over time with a period of 30-45 seconds in rodents, and loss of GFR oscillations is associated with cessation of reabsorption activities and ischemia-reperfusion injuries in the kidney, as well as systemic hypertension. To study the relationship between intracellular events and renal function, we developed a mathematical model of TGF linking metabolic regulation within PT cells to fluid handling and salt reabsorption in the nephron, using real-time transdermal GFR readings in conscious, free-moving mice of both sexes. Bifurcation analysis on model parameters revealed that due to heightened oxidative profile to supply energy for reabsorption, male PTs operate near the critical boundary of losing oscillatory behavior in the system, hence they are prone to damage upon metabolic stress. In contrast, female PTs situate further away in the parameter space and are more resilient to failure because of biases towards an anti-oxidation state. Feminized male nephrons showed an intermediate phenotype, and inhibition of peroxisome activities improved recovery post injury. Combining single-cell genomics, physiological measurement and computational modeling of renal function, this study provides a multiscale explanation for sexual dimorphism in kidney diseases. NIDDK funding: DK126925 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.