Activation of Rac1-Mineralocorticoid Receptor Pathway Contributes to Renal Injury in Salt-Loaded db/db Mice

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.

8-Aminoinosine and 8-Aminohypoxanthine Inhibit Purine Nucleoside Phosphorylase and Exert Diuretic and Natriuretic Activity

“…Instead, the Rac1 inhibitor NSC23766 mimicked the antikaliuretic effects of 8-aminoguanine ( Jackson et al, 2018 ), and in vitro, we observed that both 8-aminoguanosine and 8-aminoguanine modestly reduced Rac1 activation ( Jackson et al, 2018 ). Rac1 has been shown to directly activate mineralocorticoid receptors ( Shibata et al, 2008 ; Shibata et al, 2011 ; Hirohama et al, 2021 ), a process that would increase potassium excretion. Our hypothesis is that 8-aminoguanosine and 8-aminoguanine induce antikaliuresis by a mechanism independent of PNPase inhibition and possibly in part due to inhibition of Rac1 signaling; however, because the effects of 8-aminoguanosine and 8-aminoguanine on activated Rac1 are modest, inhibition of Rac1 may not be the main mechanism by which 8-aminoguanosine and 8-aminoguanine affect potassium excretion.…”

Prenatal Lipopolysaccharides Exposure Induces Transgenerational Inheritance of Hypertension

“…RAC1, also known as Rac Family Small GTPase 1, is involved in the development of hypertension, 16 including salt-sensitive 17 and obesity-related hypertension, 18 through activation of mineralocorticoid receptor (MR) signaling. 11,16 To determine whether the impaired urinary sodium excretion and hypertension in PLPS offspring were attributable to a high mineralocorticoid level, we measured plasma renin and serum aldosterone levels in 5-month-old rats.…”

Nonsteroidal Mineralocorticoid Receptor Antagonism by Finerenone—Translational Aspects and Clinical Perspectives across Multiple Organ Systems

“…Neurohumoral stimulation by the renin–angiotensin–aldosterone system, the sympathetic nervous system, and vasopressin contribute to permanent sodium retention and an associated extracellular volume load in the development of chronic HF and kidney failure, so MR antagonism should inhibit or delay this process [ 31 , 32 , 33 ]. Indeed, finerenone has been shown to repress increased Sgk1 levels in a murine model of CKD progression in T2D [ 34 ].…”

“…A previous investigation demonstrated that OPN is implicated in CKD progression, and its plasma levels are elevated from the early stages of CKD [ 60 ]. In a murine model of CKD progression in T2D (uninephrectomized mice with T2D fed a high-salt diet), finerenone offered protection from podocyte injury by reducing the expression of fibronectin, as well as inflammatory markers including MCP-1 and plasminogen activator inhibitor-1 (PAI-1), in glomeruli [ 34 ].…”