Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone Protects Against Acute Kidney Injury–Mediated Chronic Kidney Disease

Abstract

Acute kidney injury induced by ischemia/reperfusion (IR) is a frequent complication in hospitalized patients. Mineralocorticoid receptor antagonism has shown to be helpful against renal IR consequences; however, the potential benefit of novel nonsteroidal mineralocorticoid receptor antagonists such as finerenone has to be further explored. In this study, we evaluated the efficacy of finerenone to prevent the acute and chronic consequences of ischemic acute kidney injury. For the acute study (24 hours), 18 rats were divided into sham, bilateral renal ischemia of 25 minutes, and rats that received 3 doses of finerenone at 48, 24, and 1 hour before the ischemia. For the chronic study (4 months), 23 rats were divided into sham, rats that underwent 45 minutes of bilateral ischemia, and rats treated with finerenone at days 2 and 1 and 1 hour before IR. We found that after 24 hours of reperfusion, the untreated IR rats presented kidney dysfunction and tubular injury. Kidney injury molecule-1 and neutrophil gelatinase associated to lipolacin mRNA levels were increased. In contrast, the rats treated with finerenone displayed normal kidney function and significantly lesser tubular injury and kidney injury molecule-1 and neutrophil gelatinase associated to lipolacin levels. After 4 months, the IR rats developed chronic kidney disease, evidenced by kidney dysfunction, increased proteinuria and renal vascular resistance, tubular dilation, extensive tubule-interstitial fibrosis, and an increase in kidney transforming growth factor-β and collagen-I mRNA. The transition from acute kidney injury to chronic kidney disease was fully prevented by finerenone. Altogether, our data show that in the rat, finerenone is able to prevent acute kidney injury induced by IR and the chronic and progressive deterioration of kidney function and structure.

Vascular and inflammatory mineralocorticoid receptors in kidney disease

“…45 The protective effect of MR inhibition against the reduction in renal blood flow was mediated by increased NO production by endothelial NO synthase and the reduction of oxidative injury. [48][49][50] Moreover, it was determined that one of the mechanisms by which MR inhibition promotes adequate eNOS activation in ischaemic AKI is through a decrease in Rac 1-induced ROS generation in VSMCs, thus preventing sulfenic acid modification of the endothelin-B receptor and allowing proper signalling for eNOS activation, NO generation and thus adequate kidney perfusion. [48][49][50] Moreover, it was determined that one of the mechanisms by which MR inhibition promotes adequate eNOS activation in ischaemic AKI is through a decrease in Rac 1-induced ROS generation in VSMCs, thus preventing sulfenic acid modification of the endothelin-B receptor and allowing proper signalling for eNOS activation, NO generation and thus adequate kidney perfusion.…”

“…45 More recently, it was reported that the non-steroidal MR antagonists BR-4628 and finerenone provide similar protection against ischaemic acute kidney injury (AKI). [48][49][50] Moreover, it was determined that one of the mechanisms by which MR inhibition promotes adequate eNOS activation in ischaemic AKI is through a decrease in Rac 1-induced ROS generation in VSMCs, thus preventing sulfenic acid modification of the endothelin-B receptor and allowing proper signalling for eNOS activation, NO generation and thus adequate kidney perfusion. 48,49 Indeed, cell-specific MR KO mice revealed that MR deficiency in VSMCs confers kidney protection in models of ischaemic and nephrotoxic injury to a level similar to that observed with MR antagonists.…”

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The role of the mineralocorticoid receptor in the vasculature

“…Several recent studies have indicated a role for MR in AKI by demonstrating that MR antagonism reduces ischemia reperfusion injury in a rat model of AKI (Barrera-Chimal et al . 2016, Lattenist et al . 2017).…”

Potential Benefit of Mineralocorticoid Receptor Antagonists in Kidney Diseases

“…Experimental evidence in rodent models of acute kidney injury (AKI) supports the concept that MR contributes to vascular tone regulation [1]. The benefit of MRA in renal ischemia-reperfusion injury is associated with improved renal hemodynamics and decreased renal vascular resistance [21,22]. We recently showed that MR expressed in mouse smooth muscle cells contributes to renal injury induced by ischemia (through a mechanism involving oxidative stress and Rac1 activation) [23], as well as in acute CsA nephrotoxicity (due to increased vascular L-type calcium channel activity thereby resulting in decreased renal artery vasoconstriction and overall improvement in renal hemodynamics) [24].…”

“…In vascular cells, aldosterone increased ROS which in turn modifies the cysteinyl thiols in the eNOS-activating region of endothelin-1 B receptor to decrease endothelin-1-stimulated eNOS activity, impairing the vasodilatory pathway. These effects have repercussions on renal hemodynamics and function in kidney ischemia/reperfusion injury in both rat and mouse [21][22][23]. In rat mesangial cells, aldosterone directly stimulates superoxide anion generation, which is accompanied by an increase in NADPH oxidase activity and translocation of p47phox and p67phox to the cell membrane [28].…”