Pathological cardiac remodeling occurs early in CKD mice from unilateral urinary obstruction, and is attenuated by Enalapril

Onju Ham,Jason Roh,Hua A Jenny Lu,Kenji Tsuji,Anthony Rosenzweig,William Jin,Hui Hui Huang,Lei Lei,Ming Huang

doi:10.1038/s41598-018-34216-x

Abstract

Cardiovascular disease constitutes the leading cause of mortality in patients with chronic kidney disease (CKD) and end-stage renal disease. Despite increasing recognition of a close interplay between kidney dysfunction and cardiovascular disease, termed cardiorenal syndrome (CRS), the underlying mechanisms of CRS remain poorly understood. Here we report the development of pathological cardiac hypertrophy and fibrosis in early stage non-uremic CKD. Moderate kidney failure was induced three weeks after unilateral urinary obstruction (UUO) in mice. We observed pathological cardiac hypertrophy and increased fibrosis in UUO-induced CKD (UUO/CKD) animals. Further analysis indicated that this cardiac fibrosis was associated with increased expression of transforming growth factor β (TGF-β) along with significant upregulation of Smad 2/3 signaling in the heart. Moreover early treatment of UUO/CKD animals with an angiotensin-converting-enzyme inhibitor (ACE I), Enalapril, significantly attenuated cardiac fibrosis. Enalapril antagonized activation of the TGF-β signaling pathway in the UUO/CKD heart. In summary our study demonstrates the presence of pathological cardiac hypertrophy and fibrosis in mice early in UUO-induced CKD, in association with early activation of the TGF-β/Smad signaling pathway. We also demonstrate the beneficial effect of ACE I in alleviating this early fibrogenic process in the heart in UUO/CKD animals.

Highlights

Chronic kidney disease (CKD) is a major health problem worldwide
We further checked whether an angiotensin-converting-enzyme inhibitor (ACE I), Enalapril, has therapeutic effects in urinary obstruction (UUO)/chronic kidney disease (CKD) mice
We examined whether the reduced cardiac fibrosis in Enalapril-treated UUO-induced CKD (UUO/CKD) mice was associated with a decrease in transforming growth factor β (TGF-β)

Summary

Introduction

Chronic kidney disease (CKD) is a major health problem worldwide. According to the United States Renal Data Service’s 2015 annual report, the overall prevalence of CKD in the general population is approximately 14% (www.niddk.nih.gov/kidney-disease). UUO-induced CKD has not been reported in animal studies of type 3 and/or type 4 CRS It is not known whether pathological cardiac remodeling occurs in the presence of early mild-to-moderate renal dysfunction from UUO. A recent cross-sectional study has uncovered that even without overt cardiac dysfunction, there is still impairment in peak cardiac performance and cardiac functional reserve in asymptomatic CKD patients in the absence of other comorbidities This indicates that an insidious pre-clinical cardiac pathophysiological process may occur early on in the development of CKD35. Despite the absence of overt cardiac dysfunction significant cardiac hypertrophy and myocardial fibrosis were observed, in association with an up-regulation of the canonical TGF-β signaling cascade in the hearts of the UUO-induced CKD (UUO/CKD) mice. Blockade of the RAS with an angiotensin-converting-enzyme inhibitor (ACE I), Enalapril, significantly attenuated the UUO-induced cardiac hypertrophy and fibrosis and down-regulated TGF-β signaling

Methods

Results

Conclusion