Sex-specific
computational models of the spontaneously hypertensive rat kidneys:
factors affecting nitric oxide bioavailability. Am J Physiol Renal
Physiol 313: F174 –F183, 2017. First published March 29, 2017;
doi:10.1152/ajprenal.00482.2016.—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 (O2
) 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 O2
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 O2
production rate, are predicted to
significantly impact oxidative stress levels, but effects on NO concentration and PO2 are limited.This research was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Grant R01-DK-106102 to A. T. Layton, and by American Heart Association Grant 14GRNT20480199 to J. C. Sullivan. (R01-DK-106102 - National Institute of Diabetes and Digestive and Kidney Diseases; 14GRNT20480199 - American Heart Association)Accepted manuscrip