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CD36 and Na/K-ATPase-?1 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 ?-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 ?-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.

SUBMITTER: Kennedy DJ

PROVIDER: S-EPMC3521864 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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CD36 and Na/K-ATPase-α1 form a proinflammatory signaling loop in kidney.

Kennedy David J DJ Chen Yiliang Y Huang Wenxin W Viterna Jamie J Liu Jiang J Westfall Kristen K Tian Jian J Bartlett David J DJ Tang W H Wilson WH Xie Zijian Z Shapiro Joseph I JI Silverstein Roy L RL

Hypertension (Dallas, Tex. : 1979) 20121119 1

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 macrophag ...[more]

PMID: 23172921

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Project description:The Na/K-ATPase is an important membrane ion transporter and a signaling receptor that is essential for maintaining normal cell function. The current study examined the role of Na/K-ATPase signaling in regulating miR-29b-3p, an anti-fibrotic microRNA, in a mouse chronic kidney disease (CKD) model (5/6th partial nephrectomy or PNx). The results showed that CKD induced significant reduction of miR-29b-3p expression in the heart tissue by activation of Src and NF?B signaling in these animals. To demonstrate the role of Na/K-ATPase signaling, we also performed the PNx surgery on Na/K-ATPase ?1 heterozygous (?1+/-) mice, which expresses ~40% less Na/K-ATPase ?1 compared to their wild type littermates (WT) and exhibits deficiency in Na/K-ATPase signaling. We found that CKD did not significantly change the miR-29b-3p expression in heart tissue from the ?1+/- animals. We also found that CKD failed to activate Src and NF?B signaling in these animals. Using isolated cardiac fibroblasts from ?1+/- mice and their WT littermates, we showed that ouabain, a specific Na/K-ATPase ligand, induces decreased miR-29b-3p expression in fibroblasts isolated from WT mice, but had no effect in cells from ?1+/- mice. Inhibition of NF?B by Bay11-7082 prevented ouabain-induced miR-29b-3p reduction in WT fibroblasts. To further confirm the in vivo effect of Na/K-ATPase signaling in regulation of miR-29b-3p and cardiac fibrosis in CKD animals, we used pNaKtide, a Src inhibiting peptide derived from the sequence of Na/K-ATPase, to block the activation of Na/K-ATPase signaling. The result showed that pNaKtide injection significantly increased miR-29b-3p expression and mitigated the CKD-induced cardiac fibrosis in these animals. These results clearly demonstrated that Na/K-ATPase signaling is an important mediator in CKD that regulates miR-29b-3p expression and cardiac fibrosis, which provides a novel target for regulation of miR-29b-3p in CKD. We also demonstrate that antagonizing Na/K-ATPase signaling by pNaKtide can reduce organ fibrosis through the stimulation of tissue miR-29b-3p expression.

Dataset Information

CD36 and Na/K-ATPase-?1 form a proinflammatory signaling loop in kidney.

Publications

CD36 and Na/K-ATPase-α1 form a proinflammatory signaling loop in kidney.

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