Sex-specific computational models of the spontaneously hypertensive rat kidneys: Factors affecting nitric oxide bioavailability

The goals of this study were to 1) develop a computational model of solute transport and oxygenation in the kidney of the female spontaneously hypertensive rat (SHR), and 2) apply that model to investigate sex differences in nitric oxide (NO) levels in SHR and their effects on medullary oxygenation and oxidative stress. To accomplish these goals, we first measured NO synthase (NOS) 1 and NOS3 protein expression levels in total renal microvessels of male and female SHR. We found that the expression of both NOS1 and NOS3 is higher in the renal vasculature of females compared with males. To predict the implications of that finding on medullary oxygenation and oxidative stress levels, we developed a detailed computational model of the female SHR kidney. The model was based on a published male kidney model and represents solute transport and the biochemical reactions among O₂, NO, and superoxide (O^- ₂) in the renal medulla. Model simulations conducted using both male and female SHR kidney models predicted significant radial gradients in interstitial fluid oxygen tension (PO₂) and NO and O^- ₂ concentration in the outer medulla and upper inner medulla. The models also predicted that increases in endothelial NO-generating capacity, even when limited to specific vascular segments, may substantially raise medullary NO and PO₂ levels. Other potential sex differences in SHR, including O^- ₂ production rate, are predicted to significantly impact oxidative stress levels, but effects on NO concentration and PO₂ are limited.