title: Systemic Aldosterone, But Not Angiotensin II, Plays a Pivotal Role in the Pathogenesis of Renal Injury in Chronic Nitric Oxide-Deficient Male Rats.
abstract: Chronic inhibition of nitric oxide synthase by N(ω)-nitro-L-arginine methyl ester (L-NAME) causes progressive renal injury and systemic hypertension. Angiotensin II (Ang II) has been conventionally regarded as one of the primary causes of renal injury. We reported previously that such renal injury was almost completely suppressed by both an Ang II type I receptor blocker and an aldosterone antagonist. The aldosterone antagonist also inhibited the systemic Ang II elevation. Therefore, it remains to be elucidated whether Ang II or aldosterone directly affects the development of such renal injury. In the present study, we investigated the role of aldosterone in the pathogenesis of renal injury induced by L-NAME-mediated chronic nitric oxide synthase inhibition in male Wistar rats (aged 10 wk). Serial analyses demonstrated that the renal injury and inflammation in L-NAME-treated rats was associated with elevation of both Ang II and aldosterone. To investigate the direct effect of aldosterone on the renal injury, we conducted adrenalectomy (ADX) and aldosterone supplementation in L-NAME-treated rats. In ADX rats, aldosterone was undetectable, and renal injury and inflammation were almost completely prevented by ADX, although systemic and local Ang II and blood pressure were still elevated. Aldosterone supplementation reversed the beneficial effect of ADX. The present study indicates that aldosterone rather than Ang II plays a central and direct role in the pathogenesis of renal injury by L-NAME through inflammation, independent of its systemic hemodynamic effects.
authors: Department of Medicine and Clinical Science (T.S., K.T., H.I., J.T., S.Y., H.N., T.K.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Integrated Therapy for Chronic Kidney Disease (K.T.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and Department of Internal Medicine (S.Y., M.T.), Fukuoka Dental College, Fukuoka 814-0175, Japan.
authors: Takaichi
authors: T
authors: Suehiro
authors: Department of Medicine and Clinical Science (T.S., K.T., H.I., J.T., S.Y., H.N., T.K.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Integrated Therapy for Chronic Kidney Disease (K.T.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and Department of Internal Medicine (S.Y., M.T.), Fukuoka Dental College, Fukuoka 814-0175, Japan.
authors: Kazuhiko
authors: K
authors: Tsuruya
authors: Department of Medicine and Clinical Science (T.S., K.T., H.I., J.T., S.Y., H.N., T.K.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Integrated Therapy for Chronic Kidney Disease (K.T.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and Department of Internal Medicine (S.Y., M.T.), Fukuoka Dental College, Fukuoka 814-0175, Japan.
authors: Hirofumi
authors: H
authors: Ikeda
authors: Department of Medicine and Clinical Science (T.S., K.T., H.I., J.T., S.Y., H.N., T.K.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Integrated Therapy for Chronic Kidney Disease (K.T.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and Department of Internal Medicine (S.Y., M.T.), Fukuoka Dental College, Fukuoka 814-0175, Japan.
authors: Jiro
authors: J
authors: Toyonaga
authors: Department of Medicine and Clinical Science (T.S., K.T., H.I., J.T., S.Y., H.N., T.K.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Integrated Therapy for Chronic Kidney Disease (K.T.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and Department of Internal Medicine (S.Y., M.T.), Fukuoka Dental College, Fukuoka 814-0175, Japan.
authors: Shunsuke
authors: S
authors: Yamada
authors: Department of Medicine and Clinical Science (T.S., K.T., H.I., J.T., S.Y., H.N., T.K.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Integrated Therapy for Chronic Kidney Disease (K.T.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and Department of Internal Medicine (S.Y., M.T.), Fukuoka Dental College, Fukuoka 814-0175, Japan.
authors: Hideko
authors: H
authors: Noguchi
authors: Department of Medicine and Clinical Science (T.S., K.T., H.I., J.T., S.Y., H.N., T.K.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Integrated Therapy for Chronic Kidney Disease (K.T.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and Department of Internal Medicine (S.Y., M.T.), Fukuoka Dental College, Fukuoka 814-0175, Japan.
authors: Masanori
authors: M
authors: Tokumoto
authors: Department of Medicine and Clinical Science (T.S., K.T., H.I., J.T., S.Y., H.N., T.K.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Integrated Therapy for Chronic Kidney Disease (K.T.), Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; and Department of Internal Medicine (S.Y., M.T.), Fukuoka Dental College, Fukuoka 814-0175, Japan.
authors: Takanari
authors: T
authors: Kitazono
mesh_terms: D000315:Adrenalectomy; D000450:Aldosterone / Q000378:metabolism* / Q000494:pharmacology; D000804:Angiotensin II / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D018932:Chemokine CCL2 / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000172:deficiency; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D053495:Osteopontin / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000473:pathology; D012084:Renin-Angiotensin System / Q000187:drug effects; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000187:drug effects / Q000235:genetics
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D053495:Osteopontin; D000804:Angiotensin II; D009569:Nitric Oxide; D000450:Aldosterone; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester