Multiple metabolic hits converge on CD36 as novel mediator of tubular epithelial apoptosis in diabetic nephropathy.
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.


RESULTS
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.


CONCLUSIONS
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.
Susztak
Katalin
K
Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.
Ciccone
Emilio
E
McCue
Peter
P
Sharma
Kumar
K
Böttinger
Erwin P
EP
D000818:Animals; D017209:Apoptosis; D018955:CD36 Antigens / Q000096:biosynthesis* / Q000502:physiology; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000503:physiopathology*; D018450:Disease Progression; D004847:Epithelial Cells; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction
D018955:CD36 Antigens
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