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

Males are at greater risk for renal injury than females. This may relate to NOavailability 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 dosedependently 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 vs. 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 NOavailability such as hypercholesterolemia.