Serelaxin and augmented L‐arginine transport attenuates renal fibrosis and inflammation in experimental dilated cardiomyopathy

Abstract

IntroductionHeart failure (HF) often leads to secondary renal dysfunction. Morbidity and mortality in HF patients worsens steeply when concomitant renal injury is present and current treatments fail to rescue renal function in these patients. Reduced nitric oxide (NO) levels are associated with both heart and renal failure. We hypothesised that reduced NO bioavailability is central to the development of renal inflammation, fibrosis and ultimate failure of the kidney in HF. L‐arginine is the sole substrate for NO formation and increasing cellular L‐arginine transport can increase NO levels. Serelaxin can also increase NO levels in HF.MethodsAdult male transgenic mice (18–26 weeks of age) that develop cardiomyopathy as a result of cardiac specific overexpression of MST‐1 (DCM mice) were used. NO levels in DCM mice were increased via endothelial specific overexpression of the predominant L‐arginine transporter, cationic amino acid transporter‐1 (CAT1), and by administration of serelaxin.There were five treatment groups; wild type mice (WT; n=8), DCM mice (n=8), DCM mice overexpressing CAT1 (n=8), DCM mice administered serelaxin vehicle (20 mM sodium acetate, pH 5.0; n=8) and DCM mice administered serelaxin (500μg/kg/day; 8 weeks; subcutaneous minipumps; n=8). In all mice, cardiac structure and function were assessed via echocardiography, renal fibrosis was assessed via Masson's Trichrome staining, plasma nitrate and nitrite levels (an index of NO levels) were assessed via a commercially available ELISA kit and mRNA expression of inflammatory markers was assessed via PCR.ResultsEjection fraction was 33% less in 18 week old DCM mice than in 18 week old WT (P = 0.01). Plasma nitrate and nitrite levels were 78% less in 18 week old DCM mice than in 18 week old WT (P<0.05). Plasma nitrate and nitrite levels were normalised in 18 week old DCM mice overexpressing CAT1. Renal tubulointerstitial and glomerular fibrosis were 89% and 76% greater respectively, in 18 week old DCM mice than in age matched WT (P≤0.05). Renal tubulointerstitial and glomerular fibrosis were less (by 77 and 54% respectively; P ≤ 0.05) in 18 week old DCM mice overexpressing CAT1 compared 18 week old DCM mice that do not overexpress CAT1. Renal expression of inflammatory markers, Il6 and Il1β were less while renal expression of anti‐inflammatory marker Il‐10 was greater in the former genotype compared to the latter (all P<0.05).Renal tubulointerstitial and glomerular fibrosis were less by 46% and 45% respectively, in serelaxin treated 26 week old DCM mice compared to age matched vehicle treated DCM mice (P≤0.01). Renal mRNA expression of inflammatory marker Tnfα was 75% greater in 26 week old DCM mice compared to 26 week old WT (P<0.01). Renal Tnfα mRNA expression was 57% less in serelaxin treated 26 week old DCM mice than in 26 week old DCM mice treated with vehicle (P=0.05).ConclusionThese data indicate that augmented L‐arginine transport and serelaxin can reduce renal inflammation and fibrosis in chronic HF potentially by restoring NO levels.Support or Funding InformationNHMRC Program Grant to DK, Investigator led project grant from Novartis to NR and DKThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.