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High Fat Diet Causes Renal Fibrosis in LDLr-null Mice Through MAPK-NF-κB Pathway Mediated by Ox-LDL

Dai, Yao MD*,†; Palade, Philip PhD; Wang, Xianwei MD, PhD; Mercanti, Federico MD; Ding, Zufeng PhD; Dai, Dongsheng MD§; Mehta, Jawahar L. MD, PhD

Journal of Cardiovascular Pharmacology: February 2014 - Volume 63 - Issue 2 - p 158–166
doi: 10.1097/FJC.0000000000000035
Original Article

Background: Dyslipidemia, particularly increased LDL-cholesterol level in serum, is associated with atherosclerosis and fibrosis in different organs. This study was designed to investigate the effects of increase in LDL-cholesterol on renal fibrosis.

Methods: Wild-type (WT) and LDLr knockout (KO) mice were fed standard or high fat diet (HFD), and their kidneys were collected after 26 weeks of dietary intervention for identification of fibrosis and study of potential mechanisms. Additional studies were performed in cultured renal fibroblasts.

Results: We observed extensive and diffuse fibrosis in the kidneys of mice given HFD (P < 0.05 vs. standard chow). Fibrosis was associated with enhanced expression of fibronectin, nicotinamide adenine dinucleotide phosphate oxidases and activated p38 and p44/42 mitogen-activated protein kinases (MAPKs) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). There was evidence for accumulation of 4-hydroxynonenal, a lipid peroxidation product, in the kidneys and of ox-LDL in the arteries of LDLr KO mice given HFD. The expression of ox-LDL receptor LOX-1 and of transforming growth factor beta 1 (TGFβ1) was increased in these kidneys. All these changes were more pronounced in LDLr KO mice than in the WT mice. In in vitro studies, treatment of fibroblasts from kidneys of LDLr KO mice with ox-LDL showed intense proliferation and collagen formation (all P < 0.05, fibroblasts from WT mice kidneys). Blockade of p38 MAPK, p44/42 MAPK, or NF-κB significantly attenuated expression of profibrotic signals, collagen formation, and proliferation of fibroblasts.

Conclusions: HFD induces renal fibrosis in LDLr-null mice primarily through activation of the nicotinamide adenine dinucleotide phosphate oxidase MAPK-NF-κB pathway by ox-LDL.

Supplemental Digital Content is Available in the Text.

*Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China;

Department of Medicine, Central Arkansas Veterans Healthcare System and the University of Arkansas for Medical Sciences, Little Rock, AR;

Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR; and

§Department of Cardiology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.

Reprints: Jawahar L. Mehta, MD, PhD, Cardiovascular Division, Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72212 (e-mail:

Supported in part by funds from the Department of Veterans Affairs.

The authors report no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Received August 27, 2013

Accepted October 16, 2013

© 2014 by Lippincott Williams & Wilkins.