Multiple Metabolic Hits Converge on CD36 as Novel Mediator of Tubular Epithelial Apoptosis in Diabetic Nephropathy
Open accessAbstract
BACKGROUND: Diabetic nephropathy (DNP) is a common complication of type 1 and type 2 diabetes mellitus and the most common cause of kidney failure. While DNP manifests with albuminuria and diabetic glomerulopathy, its progression correlates best with tubular epithelial degeneration (TED) and interstitial fibrosis. However, mechanisms leading to TED in DNP remain poorly understood. METHODS AND FINDINGS: We found that expression of scavenger receptor CD36 coincided with proximal tubular epithelial cell (PTEC) apoptosis and TED specifically in human DNP. High glucose stimulated cell surface expression of CD36 in PTECs. CD36 expression was necessary and sufficient to mediate PTEC apoptosis induced by glycated albumins (AGE-BSA and CML-BSA) and free fatty acid palmitate through sequential activation of src kinase, and proapoptotic p38 MAPK and caspase 3. In contrast, paucity of expression of CD36 in PTECs in diabetic mice with diabetic glomerulopathy was associated with normal tubular epithelium and the absence of tubular apoptosis. Mouse PTECs lacked CD36 and were resistant to AGE-BSA-induced apoptosis. Recombinant expression of CD36 in mouse PTECs conferred susceptibility to AGE-BSA-induced apoptosis. CONCLUSION: Our findings suggest a novel role for CD36 as an essential mediator of proximal tubular apoptosis in human DNP. Because CD36 expression was induced by glucose in PTECs, and because increased CD36 mediated AGE-BSA-, CML-BSA-, and palmitate-induced PTEC apoptosis, we propose a two-step metabolic hit model for TED, a hallmark of progression in DNP.
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Fenofibrate may have renoprotective effects by affecting circulating lipid levels.
“Fenofibrate may have renoprotective effects by affecting circulating lipid levels.”
From Associations of Fenofibrate Therapy With Incidence and Progression of CKD in Patients With Type 2 Diabetes (2019) · cites this paper as [23]
The Results section (page unavailable) reports that a saturated free fatty acid induced apoptosis in human proximal tubular cells, providing a possible link between lipids and kidney injury. It does not examine fenofibrate, changes in circulating lipid levels, or renoprotection from treatment; the patient summary says the findings have no immediate clinical implications. (LLM, conf=0.78)
Experimental — accuracy not yet measuredIndividuals with diabetes and CKD have high levels of circulating lipids that are filtered by the kidney and accumulate in tubular epithelial cells, which may lead to fibrosis and accelerated CKD progression.
“Individuals with diabetes and CKD have high levels of circulating lipids that are filtered by the kidney and accumulate in tubular epithelial cells, which may lead to fibrosis and accelerated CKD progression.23, 24”
From Associations of Fenofibrate Therapy With Incidence and Progression of CKD in Patients With Type 2 Diabetes (2019) · cites this paper as [23]
The Results report that free fatty acid levels may be elevated in people with type 2 diabetes and that palmitic acid induced apoptosis in human proximal tubular cells. The Introduction and Discussion link tubular degeneration and interstitial fibrosis with progression of diabetic nephropathy. But the paper does not establish that circulating lipids are filtered by the kidney and accumulate in tubular cells, or that such accumulation causes fibrosis and accelerated progression. (LLM, conf=0.86)
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“Individuals with diabetes and CKD have high levels of circulating lipids that are filtered by the kidney and accumulate in tubular epithelial cells, which may lead to fibrosis and accelerated CKD progression.(23,24) Although we did not detect any evidence of effect mediation by lipid levels in the ACCORD Lipid Trial,…”
BackgroundALKHATATBEH, M. J., LINCZ, L. F., & THORNE, R. F. (2016) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2016.3069 · Cited by 44 · see citing works
- Authors
- Susztak, K., Ciccone, E., McCue, P., Sharma, K., & Böttinger, E. P.
- Affiliations
- Thomas Jefferson University (US)
- Mount Sinai Hospital (US)
- Corresponding author
- Sharma, Kumar
- Böttinger, Erwin P
- Venue
- PLoS Medicine
- Publisher
- Public Library of Science (PLoS)
- Published
- 2005-02-22
- Volume
- 2
- Issue
- 2
- Pages
- e45
- ISSN
- 1549-1277 (ISSN-L)
- 1549-1676
- PMC
- PMC549593
- OpenAlex
- W1991760543
- Cited by
- 214
- References
- 0
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 9 · 2023: 15 · 2022: 24 · 2021: 15 · 2020: 10 · 2019: 9 · 2018: 11 · 2017: 13 · 2016: 8 · 2015: 11 · 2014: 6 · 2013: 6 · 2012: 10
- FWCI
- 5.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- The Medicine Forum (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK060043, U01DK060995, R01DK056077, R01DK053867, R01DK060043)
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Keywords
- diabetic nephropathy, CD36, proximal tubular epithelial cells, advanced glycation end products, glycated albumin, palmitate, free fatty acids, Src kinase, p38 MAPK, caspase-3, high glucose, interstitial fibrosis, diabetic glomerulopathy, scavenger receptors
- MeSH terms
- Animals, Diabetic Nephropathies, Epithelial Cells, Flow Cytometry, Gene Expression Regulation, Humans, Kidney Tubules, Mice, Inbred C57BL, Polymerase Chain Reaction, Apoptosis, Disease Progression, CD36 Antigens, Mice
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