Life in the fast lane: Functional consequences of male-female dynamic differences in the renal auto-regulation of flow

Tubuloglomerular feedback (TGF) is essential for the renal auto-regulation of flow. TGF is known to induce spontaneous oscillations in single-nephron tubular fluid flow in male kidneys. However, male-female differences in this dynamic behavior have not been studied. Leveraging intravital two-photon microscopy, resting-state magnetic resonance imaging, ultrasound-based and transdermal recordings, we found TGF-mediated oscillations across spatial scales in the rodent kidney, from single-nephron to whole-organ levels, and that male kidneys exhibited higher operating frequencies than females. To understand the mechanisms involved, we developed a dynamical systems model of TGF that agrees with physiological observations. Analysis of the mathematical model indicated that higher reabsorption rate and fluid flow efficiency in male proximal tubules not only result in higher frequencies, but also render male nephrons more susceptible to lose TGF-mediated oscillations. Furosemide abolished TGF-mediated oscillations in male kidneys and upregulated tubular injury marker KIM-1, suggesting that the propensity to lose TGF-mediated oscillations underlies the heightened risk for injury in males. Our analysis also indicated that SGLT-2 inhibition confers renoprotection by preserving TGF-mediated oscillations in hyperglycemia. Combining quantitative imaging and mathematical modeling, this study provides mechanistic insights into the transition from normal physiology to pathophysiology in the kidney.