title: Male gender increases sensitivity to renal injury in response to cholesterol loading.
abstract: Males are at greater risk for renal injury than females. This may relate to nitric oxide (NO) availability, because female rats have higher renal endothelial NO synthase (NOS) levels. Previously, our laboratory found susceptibility to proteinuria induced by NOS inhibition in male compared with 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 wk. Cholesterol feeding dose dependently increased proteinuria in both 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(-1). mg protein(-1); 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 female rats. This may explain why male rats are more sensitive to renal injury by factors that decrease NO availability, such as hypercholesterolemia.
authors.affiliation: Department of Nephrology, University Medical Center, 3508 GA Utrecht, The Netherlands.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Attia
authors.forename: Roel
authors.initials: R
authors.lastname: Goldschmeding
authors.forename: Mahmoud A
authors.initials: MA
authors.lastname: Attia
authors.forename: Peter
authors.initials: P
authors.lastname: Boer
authors.forename: Hein A
authors.initials: HA
authors.lastname: Koomans
authors.forename: Jaap A
authors.initials: JA
authors.lastname: Joles
mesh_terms: D000818:Animals; D002791:Cholesterol, Dietary; D004195:Disease Models, Animal; D004435:Eating; D005260:Female; D006937:Hypercholesterolemia / Q000097:blood / Q000139:chemically induced; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011507:Proteinuria / Q000139:chemically induced / Q000503:physiopathology; D051381:Rats; D012737:Sex Factors; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D014556:Urine / Q000737:chemistry
chemical_list: D002791:Cholesterol, Dietary; D017392:Thiobarbituric Acid Reactive Substances; D019001:Nitric Oxide Synthase