Activation of renin-angiotensin system is involved in dyslipidemia-mediated renal injuries in apolipoprotein E knockout mice and HK-2 cells

Jie Ni,Xiong-Zhong Ruan,Kun-Ling Ma,Lin-Li Lv,Chang-Xian Wang,Jing Liu,Yang Zhang,Ya-Xi Chen,Bi-Cheng Liu,Hai-Feng Ni

doi:10.1186/1476-511x-12-49

Abstract

BackgroundDyslipidemia and activation of renin-angiotensin system (RAS) contribute to the progression of chronic kidney disease (CKD). This study investigated possible synergistic effects of intrarenal RAS activation with hyperlipidemia in renal injuries.MethodsApolipoprotein knockout mice were fed with normal chow diet (control) or high fat diet (HF group) for eight weeks. Human proximal tubular epithelial cell line (HK-2) was treated without (control) or with cholesterol (30 μg/ml) plus 25-hydroxycholesterol (1 μg/ml) (lipid group) for 24 hours. The plasma lipid profile and RAS components were determined by clinical biochemistry assay and radiommunoassay, respectively. Collagen deposition in kidneys was evaluated by Masson-staining. The gene and protein expressions of molecules involved in RAS components and biomarkers of epithelial mesenchymal transition (EMT) were examined by real-time PCR, immunochemical staining, and Western blot.ResultsThe mice fed with high-fat diet showed significant hyperlipidemia with collagen deposition in renal tubular interstitium compared to controls. The plasma levels of renin, angiotensin I, and angiotensin II were no difference in two groups. However, the kidneys of HF group showed up-regulated RAS components, which were positively associated with increased plasma levels of triglyceride, total cholesterol, and LDL. These effects were further confirmed by in vitro studies. Lipid loading induced HK-2 cells underwent EMT, which was closely associated with the increased expressions of intracellular RAS components.ConclusionsLocal RAS activation was involved in hyperlipidemia-mediated renal injuries, suggesting that there are synergistic effects resulting from RAS activation with hyperlipidemia that accelerates the progression of CKD.

Highlights

Dyslipidemia and activation of renin-angiotensin system (RAS) contribute to the progression of chronic kidney disease (CKD)
A growing body of evidence shows that injured renal tubular epithelial cells have been implicated in increasing kidney matrix-producing fibroblasts and myofibroblasts populations through the process of epithelial–mesenchymal transition (EMT), leading to renal tubular interstitial fibrosis (TIF) [1] and inevitable progressive chronic kidney disease (CKD) [2]
There was no difference in the plasma concentrations of renin, angiotensin I, and angiotensin II between the two groups; prorenin levels were significantly reduced in the High fat (HF) group compared with the control group (Figure 2A and 2B)

Summary

Introduction

Dyslipidemia and activation of renin-angiotensin system (RAS) contribute to the progression of chronic kidney disease (CKD). The exact mechanisms for dyslipidemia-mediated renal injuries have not been entirely elucidated. The activation of the RAS has been implicated in the progression of CKD [6]. Angiotensin II, via the AT1-dependent pathway, causes cell proliferation, production of pro-inflammatory mediators, and extracellular matrix synthesis, all of which facilitates kidney damage and accelerates the progression of CKD [7,8,9]. Angiotensin II regulates gene expression of bioactive substances and activates multiple intracellular signaling pathways, all of which may contribute to renal injury [6]. The intracellular synthesis pathway of RAS in renal tubular cells and its stimuli remain unclear

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Conclusion