N-Acetylcysteine Attenuates\xa0the Development of Renal Fibrosis in Transgenic Mice with Dilated Cardiomyopathy

Beverly Giam,Niwanthi W Rajapakse,David M Kaye,Xiao-Jun Du,Sanjaya Kuruppu,Duncan Horlock,Po-Yin Chu,A Ian Smith,Francine Z Marques,Helen Kiriazis,April Fiedler

doi:10.1038/s41598-017-17927-5

Abstract

Mechanisms underlying the renal pathology in cardiorenal syndrome (CRS) type 2 remain elusive. We hypothesised that renal glutathione deficiency is central to the development of CRS type 2. Glutathione precursor, N-acetylcysteine (NAC;40 mg/kg/day; 8 weeks) or saline were administered to transgenic mice with dilated cardiomyopathy (DCM) and wild-type (WT) controls. Cardiac structure, function and glutathione levels were assessed at the end of this protocol. Renal fibrosis, glutathione content, expression of inflammatory and fibrotic markers, and function were also evaluated. In both genotypes, NAC had minimal effect on cardiac glutathione, structure and function (P ≥ 0.20). In NAC treated DCM mice, loss of glomerular filtration rate (GFR), tubulointerstitial and glomerular fibrosis and renal oxidised glutathione levels were attenuated by 38%, 99%, 70% and 52% respectively, compared to saline treated DCM mice (P ≤ 0.01). Renal expression of PAI-1 was greater in saline treated DCM mice than in WT mice (P < 0.05). Renal PAI-1 expression was less in NAC treated DCM mice than in vehicle treated DCM mice (P = 0.03). Renal IL-10 expression was greater in the former cohort compared to the latter (P < 0.01). These data indicate that normalisation of renal oxidized glutathione levels attenuates PAI-1 expression and renal inflammation preventing loss of GFR in experimental DCM.

Highlights

Chronic HF is associated with systemic inflammation and augmented levels of circulating pro-inflammatory cytokines such as tumour necrosis factor alpha (TNF-α) and interleukin (IL-)[15,6], which can deplete glutathione levels[7,8]
We found that experimental dilated cardiomyopathy (DCM) arising from cardiac specific overexpression of Mst[1] was associated with renal fibrosis, inflammation and loss of glomerular filtration rate (GFR)
Consistent with this, we found that loss of GFR was prevented in DCM mice treated with NAC but not saline vehicle

Summary

Introduction

Chronic HF is associated with systemic inflammation and augmented levels of circulating pro-inflammatory cytokines such as tumour necrosis factor alpha (TNF-α) and interleukin (IL-)[15,6], which can deplete glutathione levels[7,8]. An unpaired t-test was used to compare baseline fibrosis vs fibrosis at the end of NAC treatment in DCM mice. The association between renal inflammation, glutathione levels and renal function has not been investigated in the setting of CRS type 2. We tested that hypothesis that renal glutathione deficiency is central to the progression of renal inflammation and fibrosis leading to loss of renal function in CRS type 2. Current experimental models of HF, such as that due to myocardial infarction simulated by coronary artery ligation do not appear to develop the level of renal injury and dysfunction observed in patients with CRS type 220,21. In the present study, we aimed to validate a new mouse model of CRS type 2 and loss of renal function and inflammation were assessed in a transgenic mouse model of dilated cardiomyopathy (DCM)

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