Abstract
Albuminuria is an early marker of renovascular damage associated to an increase in oxidative stress. The Munich Wistar Frömter (MWF) rat is a model of chronic kidney disease (CKD), which exhibits endothelial dysfunction associated to low nitric oxide availability. We hypothesize that the new highly selective, non-steroidal mineralocorticoid receptor (MR) antagonist, finerenone, reverses both endothelial dysfunction and microalbuminuria. Twelve-week-old MWF (MWF-C; MWF-FIN) and aged-matched normoalbuminuric Wistar (W-C; W-FIN) rats were treated with finerenone (FIN, 10 mg/kg/day p.o.) or vehicle (C) for 4-week. Systolic blood pressure (SBP) and albuminuria were determined the last day of treatment. Finerenone lowered albuminuria by >40% and significantly reduced SBP in MWF. Aortic rings of MWF-C showed higher contractions to either noradrenaline (NA) or angiotensin II (Ang II), and lower relaxation to acetylcholine (Ach) than W-C rings. These alterations were reversed by finerenone to W-C control levels due to an upregulation in phosphorylated Akt and eNOS, and an increase in NO availability. Apocynin and 3-amino-1,2,4-triazole significantly reduced contractions to NA or Ang II in MWF-C, but not in MWF-FIN rings. Accordingly, a significant increase of Mn-superoxide dismutase (SOD) and Cu/Zn-SOD protein levels were observed in rings of MWF-FIN, without differences in p22phox, p47phox or catalase levels. Total SOD activity was increased in kidneys from MWF-FIN rats. In conclusion, finerenone improves endothelial dysfunction through an enhancement in NO bioavailability and a decrease in superoxide anion levels due to an upregulation in SOD activity. This is associated with an increase in renal SOD activity and a reduction of albuminuria.
Highlights
Albuminuria is a hallmark of both early kidney damage and progression of chronic kidney disease (CKD) in nondiabetic and diabetic subjects (Eckardt et al, 2013; Carrero et al, 2017)
Systolic blood pressure (SBP) and MAP were significantly higher in Munich Wistar Frömter (MWF) at the end of the study compared to aged-matched W (Figure 1A and Table 1)
Finerenone lead to a significant reduction (>40%) in albuminuria in the MWF model (Figure 1B), while normoalbuminuria was not affected in Wistar rats
Summary
Albuminuria is a hallmark of both early kidney damage and progression of chronic kidney disease (CKD) in nondiabetic and diabetic subjects (Eckardt et al, 2013; Carrero et al, 2017). In patients with diabetes mellitus and hypertension, increased urinary albumin excretion (UAE) in a range even below the lower clinical cut of defining albuminuria (i.e., 30 mg/24 h) predicts cardiovascular events and a continuous relationship between cardiovascular and non-cardiovascular mortality has been reported (Piepoli et al, 2016). Patients with albuminuria exhibit a widespread vascular damage (Fogarty et al, 2000; Freedman et al, 2008) due to a systemic endothelial disorder affecting the glomerular endothelium (Deckert et al, 1989; Stehouwer and Smulders, 2006). Endothelial dysfunction has been linked to an increased glomerular and vascular oxidative stress in patients with albuminuria (Vaziri et al, 2002; Satoh, 2012). Endothelial dysfunction associated to oxidative stress may represent a common pathophysiological mechanism leading to both cardiovascular and renal disease
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