CD36 and Na/K-ATPase-α1 Form a Pro-inflammatory Signaling Loop in Kidney

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 61; no. 1; pp. 216 - 224
• Main Authors: Kennedy, David J., Chen, Yiliang, Huang, Wenxin, Viterna, Jamie, Liu, Jiang, Westfall, Kristen, Tian, Jian, Bartlett, David J., Wilson Tang, W. H., Xie, Zi-jian, Shapiro, Joseph I., Silverstein, Roy L.
• Format: Journal Article
• Language: English
• Published: 19.11.2012
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.112.198770

Pro-atherogenic, hyperlipidemic states demonstrate increases in circulating ligands for scavenger receptor CD36 (e.g. oxidized LDL (oxLDL)) and the Na/K-ATPase (e.g. 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 (PTC) and their associated macrophages and thereby facilitates development of chronic inflammation and tubulointerstitial fibrosis. ApoE −/− and apoE −/− /cd36 −/− mice were fed a high-fat diet (HFD) for up to 32 weeks and examined for physiologic and histologic changes in renal function. Compared to apoE −/− , apoE −/− /cd36 −/− mice had improved creatinine clearance and blood pressure which corresponded histologically to less glomerular and tubulointerstitial macrophage accumulation, foam cell formation, oxidant stress, and interstitial fibrosis. Co-IP and a cell surface fluorescence-based crosslinking assay showed CD36 and Na/K-ATPase α-1 co-localized in PTC 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 PTC. Cell-free conditioned media from PTC treated with oxLDL or ouabain increased macrophage migration. OxLDL, ouabain, or plasma isolated from HFD-fed mice stimulated reactive oxygen species production in PTC 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 PTC and their associated macrophages which facilitates the development of chronic inflammation, oxidant stress, and fibrosis underlying the renal dysfunction common to pro-atherogenic, hyperlipidemic states.