N-acetylcysteine Reverses Established Renal Fibrosis and Restores Renal Function in a Mouse Model of Dilated Cardiomyopathy

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

Research output: Contribution to conferenceAbstract

Abstract

Introduction: Renal dysfunction occurring secondary to heart failure (HF) involves a complex interplay of mechanisms, among which renal fibrosis is a key culprit. It has been shown that levels of glutathione, our body’s predominant antioxidant, when augmented contributes to fibrosis development in cardiac and renal dysfunction. Here, we hypothesize that restoring glutathione capacity can reverse renal fibrosis and improve renal function in mice with HF. Methods: Eighteen week old mice with dilated cardiomyopathy (DCM;n=16) and age-matched littermate controls (WT;n=18) were used. All mice received treatment with either N-acetylcysteine (NAC;40mg/kg/day), a precursor for glutathione, or saline for a period of 8 weeks via subcutaneously implanted minipumps. At study end, cardiac and renal structure, function, and fibrosis, renal gene expression, and renal glutathione content were assessed in all mice. In a separate cohort, these data were collected in 18-week-old mice (WT;n=16, DCM;n=17) for the evaluation of baseline parameters. Results: At baseline, mean LV wall thickness and ejection fraction were 23% and 36% less respectively, in DCM mice than WT (P<0.001). This was accompanied by 88%, 73% and 40% greater levels of tubulointerstitial fibrosis, glomerular fibrosis, and renal oxidised glutathione content respectively, in DCM mice compared to WT (P≤0.05). After 8 weeks of treatment, renal oxidised glutathione content was 52% less in NAC-treated DCM mice than untreated DCM mice (P<0.01). This was associated with 99% and 70% less tubulointerstitial and glomerular fibrosis respectively, in NAC-treated DCM mice compared to untreated DCM mice (P<0.001). Of note, tubulointerstitial and glomerular fibrosis were less in NAC-treated DCM mice compared to levels at baseline (P<0.05). Lastly, glomerular filtration rate (GFR) was 38% greater in NAC-treated DCM mice compared to untreated DCM mice (P<0.01). Importantly GFR in NAC-treated DCM mice was comparable to that of age-matched WT mice (P=0.99). Treatment with NAC however, had no effect on cardiac structure or function in DCM mice (P≥0.20).
Original languageEnglish
Number of pages1
Publication statusPublished - 14 Nov 2017
Externally publishedYes

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