title: CD36 and Na/K-ATPase-α1 form a proinflammatory signaling loop in kidney.
abstract: Proatherogenic, hyperlipidemic states demonstrate increases in circulating ligands for scavenger receptor CD36 (eg, oxidized low-density lipoprotein [oxLDL]) and the Na/K-ATPase (eg, cardiotonic steroids). These factors increase inflammation, oxidative stress, and progression of chronic kidney disease. We hypothesized that diet-induced obesity and hyperlipidemia potentiate a CD36/Na/K-ATPase-dependent inflammatory paracrine loop between proximal tubule cells (PTCs) and their associated macrophages and thereby facilitate development of chronic inflammation and tubulointerstitial fibrosis. ApoE(-/-) and apoE(-/-)/cd36(-/-) mice were fed a high-fat diet for ≤32 weeks and examined for physiologic and histologic changes in renal function. Compared with apoE(-/-), apoE(-/-)/cd36(-/-) mice had improved creatinine clearance and blood pressure which corresponded histologically with less glomerular and tubulointerstitial macrophage accumulation, foam cell formation, oxidant stress, and interstitial fibrosis. Coimmunopreciptation and a cell surface fluorescence-based crosslinking assay showed that CD36 and Na/K-ATPase α-1 colocalized in PTCs and macrophages, and this association was increased by oxLDL or the cardiotonic steroid ouabain. OxLDL and ouabain also increased activation of Src and Lyn in PTCs. Cell-free conditioned medium from PTCs treated with oxLDL or ouabain increased macrophage migration. OxLDL, ouabain, or plasma isolated from high-fat diet-fed mice stimulated reactive oxygen species production in PTCs, which was inhibited by N-acetyl-cysteine, apocynin, or Na/K-ATPase α-1 knockdown. These data suggest that ligands generated in hyperlipidemic states activate CD36 and the Na/K-ATPase and potentiate an inflammatory signaling loop involving PTCs and their associated macrophages, which facilitates the development of chronic inflammation, oxidant stress, and fibrosis underlying the renal dysfunction common to proatherogenic, hyperlipidemic states.
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Kennedy
authors.forename: Yiliang
authors.initials: Y
authors.lastname: Chen
authors.forename: Wenxin
authors.initials: W
authors.lastname: Huang
authors.forename: Jamie
authors.initials: J
authors.lastname: Viterna
authors.forename: Jiang
authors.initials: J
authors.lastname: Liu
authors.forename: Kristen
authors.initials: K
authors.lastname: Westfall
authors.forename: Jian
authors.initials: J
authors.lastname: Tian
authors.forename: David J
authors.initials: DJ
authors.lastname: Bartlett
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.forename: Zijian
authors.initials: Z
authors.lastname: Xie
authors.forename: Joseph I
authors.initials: JI
authors.lastname: Shapiro
authors.forename: Roy L
authors.initials: RL
authors.lastname: Silverstein
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism*; D002448:Cell Adhesion; D002465:Cell Movement; D059305:Diet, High-Fat / Q000009:adverse effects; D005355:Fibrosis; D006949:Hyperlipidemias / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009765:Obesity / Q000209:etiology / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D051436:Renal Insufficiency, Chronic / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
chemical_list: D018955:CD36 Antigens; D000254:Sodium-Potassium-Exchanging ATPase