title: eNOS knockout mice with advanced diabetic nephropathy have less benefit from renin-angiotensin blockade than from aldosterone receptor antagonists.
abstract: While blockade of the renin angiotensin system (RAS) is beneficial in treating many patients with diabetic nephropathy, some patients show a poor response. We hypothesized that the poor response of RAS blockade is attributed to inability to stimulate endothelial nitric oxide. Recently, we reported that diabetic eNOS knockout (KO) mice develop advanced diabetic nephropathy similar to human disease. Here, we tested the hypothesis that blockade of the RAS would be less beneficial in this model than in diabetic wild-type mice. Both enalapril and telmisartan were less effective at reducing renal injury in diabetic eNOSKO mice compared with diabetic wild-type mice. Blood pressure was only transiently reduced by these treatments in diabetic eNOSKO mice and later returned to levels similar to that of untreated diabetic eNOSKO mice. Serum aldosterone tended to be paradoxically higher with enalapril or telmisartan in diabetic eNOSKO mice, whereas these treatments tended to lower aldosterone in diabetic wild-type mice. The pathogenic role of aldosterone was demonstrated by the evidence that spironolactone significantly reduced blood pressure and prevented renal injury. In addition, a higher dose of enalapril also failed to prevent hypertension and renal injury in diabetic eNOSKO mice. In conclusion, an impaired endothelial NO response could lessen the benefit of RAS inhibition in diabetic renal disease. Aldosterone blockade may provide superior protection in this setting.
authors.affiliation: Division of Nephrology, University of Florida, Gainesville, Florida, USA.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kosugi
authors.forename: Marcelo
authors.initials: M
authors.lastname: Heinig
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakayama
authors.forename: Seiichi
authors.initials: S
authors.lastname: Matsuo
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nakagawa
mesh_terms: D000450:Aldosterone / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D003928:Diabetic Nephropathies / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D016503:Drug Delivery Systems; D004656:Enalapril / Q000494:pharmacology / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000451:Mineralocorticoid Receptor Antagonists; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000187:drug effects; D013311:Streptozocin; D000077333:Telmisartan; D017211:Treatment Failure
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001565:Benzoates; D007004:Hypoglycemic Agents; D000451:Mineralocorticoid Receptor Antagonists; D000450:Aldosterone; D013311:Streptozocin; D004656:Enalapril; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D000077333:Telmisartan