CD36 and Na/K-ATPase-α1 Form a Proinflammatory Signaling Loop in Kidney
Open accessAbstract
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.
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The type 2 scavenger receptor CD36 and Na/K-ATPase have emerged as key molecules in mediating the renal inflammation triggered by obesity in mice.
“The type 2 scavenger receptor, CD36, and Na/K-ATPase have also emerged as key molecules in mediating the renal inflammation triggered by obesity in mice (68).”
From Obesity-Associated Hypertension: Recent Progress in Deciphering the Pathogenesis (2014) · cites this paper as [68]
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Obesity-Associated Hypertension: Recent Progress in Deciphering the Pathogenesis
Rahmouni, K. (2014) · Hypertension · doi:10.1161/hypertensionaha.114.00920 · Cited by 150 · see citing works
- Authors
- Kennedy, D. J., Chen, Y., Huang, W., Viterna, J., Liu, J., Westfall, K., Tian, J., Bartlett, D. J., Tang, W. H. W., Xie, Z., Shapiro, J. I., & Silverstein, R. L.
- Affiliations
- Cleveland Clinic (US)
- ORCID
- Venue
- Hypertension
- Published
- 2013-01
- Volume
- 61
- Issue
- 1
- Pages
- 216-224
- ISSN
- 0194-911X (ISSN-L)
- 1524-4563
- PMC
- PMC3521864
- OpenAlex
- W2105901029
- Cited by
- 101
- References
- 57
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 9 · 2023: 9 · 2022: 9 · 2021: 9 · 2020: 11 · 2019: 7 · 2018: 6 · 2017: 7 · 2016: 5 · 2015: 10 · 2014: 4 · 2013: 2
- FWCI
- 4.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hypertension (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (7r01hl109015-04, UL1TR000439)
- National Heart, Lung, and Blood Institute (P01HL046403, HL-072942, R01HL-109015, R01 HL09015, P01HL072942, R01HL111614, P01HL087018)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- CD36, chronic kidney disease, hyperlipidemia, diet-induced obesity, oxidized LDL, ouabain, cardiac glycosides, proximal tubular epithelial cells, renal macrophages, tubulointerstitial fibrosis, oxidative stress, paracrine signaling, macrophage migration
- MeSH terms
- Sodium-Potassium-Exchanging ATPase, Animals, Cell Adhesion, Cell Movement, Fibrosis, Hyperlipidemias, Inflammation, Kidney, Macrophages, Obesity, Signal Transduction, Oxidative Stress, CD36 Antigens, Mice, Renal Insufficiency, Chronic, Diet, High-Fat
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