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Am J Physiol Renal Physiol (December 17, 2002). doi:10.1152/ajprenal.00009.2002
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Articles in PresS, published online ahead of print December 17, 2002
Am J Physiol Renal Physiol, 10.1152/ajprenal.00009.2002
Submitted on January 7, 2002
Accepted on November 27, 2002

Male gender increases the sensitivity to renal injury in response to cholesterol loading

Diana M. Attia1, Roel Goldschmeding2, Mahmoud A. Attia3, Peter Boer1, Hein A. Koomans1, and Jaap A. Joles1*

1 Department of Nephrology and Hypertension, University Medical Center (UMC), Utrecht, The Netherlands
2 Department of Pathology, University Medical Center (UMC), Utrecht, The Netherlands
3 Department of Pathology, Centre International de Toxicologie (CIT), Miserey, France

* To whom correspondence should be addressed. E-mail: j.a.joles{at}med.uu.nl.

Males are at greater risk for renal injury than females. This may relate to NO-availability because female rats have higher renal endothelial NO synthase (NOS) levels. Previously, we found susceptibility to proteinuria induced by NOS inhibition in male as compared to female rats. Dyslipidemia and hypercholesterolemia dose-dependently decreased renal NOS activity and caused renal injury in female rats. We hypothesized that exposure of male rats to hypercholesterolemia would lead to more renal injury in male than in female rats, due to an a priori lower renal NO-system. Female and male rats were fed no, low-dose, or high-dose cholesterol for 24 weeks. Cholesterol feeding dose-dependently increased proteinuria both in female and male rats, but male rats developed more proteinuria at similar plasma cholesterol (p<0.001). Control males had lower renal NOS activity than control females (4.44±0.18 versus 7.46±0.37 pmol/min/mg protein; p<0.05) and cholesterol feeding decreased renal NOS activity in males and in females (p<0.05). Cholesterol-fed males developed significantly more vascular, glomerular and tubulointerstitial monocyte/macrophage influx and injury than females. Thus, under baseline conditions male rats have lower renal NOS activity than females. This may explain why male rats are more sensitive to renal injury by factors that decrease NO-availability such as hypercholesterolemia.




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