Hypertension-induced renal fibrosis and spironolactone response vary by rat strain and mineralocorticoid receptor gene expression

Abstract

I In nt tr ro od du uc ct ti io on n. . Aldosterone promotes renal fibrosis via the mineralocorticoid receptor (MR), thus contributing to hypertension-induced nephropathy. We investigated whether MR gene expression influences renal fibrosis and MR antagonist response in a two-kidney, one-clip hypertensive rat model. M Ma at te er ri ia al ls s a an nd d m me et th ho od ds s. . Brown Norway (BN), Lewis, and ACI rats were randomised to spironolactone 20 mg/kg/day or water by gavage, starting four weeks after left renal artery clipping. Blood pressure was measured bi-weekly by tail cuff. After eight weeks of treatment, right kidneys were removed and examined for fibrosis and gene expression. Rats of each strain undergoing no intervention served as controls. R Re es su ul lt ts s. . Blood pressure increased similarly among strains after clipping and was unaffected by spironolactone. Hypertension caused the greatest renal fibrosis in BN rats (p < 0.001 by ANOVA compared to other strains). Real-time PCR analysis showed greater renal collagen type I and MR gene expression in untreated, hypertensive BN rats (both p < 0.05 compared to other strains). Spironolactone attenuated fibrosis, with similar fibrosis among strains of spironolactone-treated rats. C Co on nc cl lu us si io on n. . Hypertension-induced renal fibrosis was greatest in rats with the highest MR gene expression. Spironolactone abolished inter-strain differences in fibrosis. Our data suggest that MR genotype may influence aldosterone-induced renal damage, and consequently, renal response to aldosterone antagonism. IntroductionAldosterone contributes to hypertension-induced renal damage by promoting renal inflammation, glomerular injury, and abnormal accumulation of fibrillar collagens.1-3 The renal effects of aldosterone are believed to be mediated via the mineralocorticoid receptor (MR; NR3C2), a member of the nuclear receptor superfamily.4 MR antagonism with spironolactone has been shown to provide renal protective effects through mechanisms independent of blood pressure reduction. [5][6][7] There is evidence of inter-patient variability in susceptibility to hypertension-induced renal damage. 8,9 In addition, we have previously described inter-patient differences in response to MR antagonists.10 Polymorphisms in genes encoding for proteins involved in the pathogenesis of hypertension-induced organ damage are believed to contribute to the inter-patient variability in target organ complications.11 Similarly, inter-patient differences in drug response may be largely attributed to genetic polymorphisms for proteins involved in drug disposition or pharmacodynamics.12 Given that the MR is expressed in renal tissue and that MR antagonists attenuate aldosteronemediated injury, the MR gene is a potential candidate for influencing response to aldosterone and MR antagonists. 2,4 We hypothesised that aldosterone-mediated effects on the kidney and spironolactone response vary by MR genotype. We exposed three strains of normotensive inbred rats to renovascula...

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“…Masson's staining showed that the renal fibrosis was significantly elevated in 2K1C rats compared with Sham rats, which was consistent with previous findings ( 33 – 35 ). Intraperitoneally administrated with high dose of vaccarin or captopril abrogated the fibrosis in the right kidney in 2K1C rats ( Fig.…”

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“…-in the heart of rodents with myocardial infarction (Milik et al, 2007;Takeda et al, 2007), with diastolic heart failure (Ohtani et al, 2007), or with hypertension (Silvestre et al, 2000;Konishi et al, 2003); -in vessels of hypertensive animals (SHR) (DeLano and Schmid-Schonbein, 2004) or vascular cells in a model of normal aging (30-month-old Fisher344 cross-bred Brown Norway rats) (Krug et al, 2010); -in hypoxic pulmonary artery vascular endothelial cells (Maron et al, 2014); -in the kidney of Brown Norway rats (Cavallari et al, 2008) and in the renal collecting duct of spontaneously hypertensive rats (Farman and Bonvalet, 1985); -in adipose tissue from diabetic animal models (obese db/db and ob/ob mice, HFD) (Guo et al, 2008;Hirata et al, 2009Hirata et al, , 2012; in kidney from db/db mice and streptozotocin-treated rats (Guo et al, 2006); -in skin of mice with ultraviolet irradiation and metabolic syndrome .…”

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“…Aldosterone administration in a connection with a high-salt diet induced massive proteinuria and resulted in less intense immunostaining for nephrin, which suggest that aldosterone-induced proteinuria and renal damage are attributable to the injury of podocytes which play key role in the development of albuminuria and the progression of kidney disease [45,57]. Aldosterone contributes to hypertension-induced renal damage by promoting renal inflammation, glomerular injury, and abnormal accumulation of fibrillar collagens [58,59].…”