Activation of Rac1-Mineralocorticoid Receptor Pathway Contributes to Renal Injury in Salt-Loaded db/db Mice. Issue 1 (July 2021)

• Record Type: Journal Article
• Authors: Hirohama, Daigoro; Nishimoto, Mitsuhiro; Ayuzawa, Nobuhiro; Kawarazaki, Wakako; Fujii, Wataru; Oba, Shigeyoshi; Shibata, Shigeru; Marumo, Takeshi; Fujita, Toshiro
• Is Part Of: Hypertension. Volume 78:Issue 1(2021)
• Publication Date: 2021-07
• Subjects: aldosterone -- diabetic kidney disease -- hypertension -- mineralocorticoid receptor -- sodium; Hypertension -- Periodicals; Hypertension -- Treatment -- Periodicals; 616.132005
• DOI: 10.1161/HYPERTENSIONAHA.121.17263
• Languages: English
• ISSNs: 0194-911X

Abstract

Abstract : The progression of diabetic kidney disease (DKD), a leading cause of end-stage kidney disease, involves mineralocorticoid receptor (MR) activation. We previously identified crosstalk between the small guanosine triphosphatase (GTPase) RAS-related C3 botulinus toxin substrate 1 (Rac1) and MR, but the role of Rac1-MR pathway activation in the progression of DKD is not clear. We performed uninephrectomy on type 2 diabetic mouse models, db/db (UNx-high salt [HS] db/db ), and their lean control, db/m (UNx-HS db/m ), at 4-week postpartum, and fed them a high-salt diet for 10 weeks. To evaluate the involvement of the Rac1-MR pathway in the DKD progression, we investigated the effects of the nonsteroidal MR antagonist, finerenone, and the Rac1 inhibitor, NSC23766, on blood pressure and glomerular injury in UNx-HS db/db mice. UNx-HS db/db mice with hyperaldosteronism showed hypertension and hypokalemia with increased cleaved α-epithelial sodium channel expressions and massive albuminuria, accompanied by glomerular injury with nodular lesions, which is a characteristic finding in human diabetic nephropathy. Expressions of active Rac1 and serum-and glucocorticoid-induced protein kinase 1 (Sgk1), a downstream molecule of MR signaling, in the renal cortex and isolated glomeruli, significantly elevated in UNx-HS db/db mice, associated with intense staining of active Rac1 in glomerular podocytes, but both hypertension and renal injury were ameliorated by NSC23766 and finerenone, associated with Sgk1 inhibition, suggesting that Rac1-MR activation contributes to hypertension and podocyte injury. In conclusion, salt-induced activation of Rac1-MR pathway in distal tubules and glomeruli is involved in DKD progression through hypertension and glomerular injury, respectively. This finding highlights MR antagonism along with Rac1 inhibition as a novel strategy for DKD treatment. Abstract : Supplemental Digital Content is available in the text.