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Publication

Multiple Metabolic Hits Converge on CD36 Scavenger Receptor as Novel Mediator of Tubular Epithelial Apoptosis in Diabetic Nephropathy

Authors Katalin Susztak*, Emilio Ciccone†, Kumar Sharma†, ‡, Erwin P. Böttinger*, ‡ Submitted By Erwin Bottinger on 5/3/2004 Status Published Journal PLoS medicine / Public Library of Science Year 2005 Date Published 2/1/2005 Volume : Pages 2 : 152 - 161 PubMed Reference Abstract Diabetic nephropathy (DNP) is a common chronic complication of type 1 and type 2 diabetes mellitus and the most common cause of end-stage renal failure. While DNP manifests with albuminuria and characteristic diabetic glomerulopathy, its progression to renal failure correlates best with tubular epithelial degeneration (TED) and interstitial fibrosis (IF). However, mechanisms leading to TED in DNP remain poorly understood. We found that expression of class B scavenger receptor CD36 coincided with proximal tubular epithelial cells (PTEC) apoptosis and TED in human DNP. High ambient glucose stimulated cell surface expression of CD36 in PTEC. CD36 expression was necessary and sufficient to mediate PTEC apoptosis induced by glycated albumins (AGE-BSA) and free fatty acid (FFA) through activation of proapoptotic p38 MAPK signaling. In contrast, paucity of expression of Cd36 in PTEC in diabetic mice with diabetic glomerulopathy was associated with absence of tubular apoptosis and normal tubular epithelium. Mouse PTEC lacked Cd36 and were resistant to AGE-BSA induced apoptosis. Recombinant expression of CD36 in mouse PTECs confered susceptibility to AGE-BSA-induced apoptosis. In conclusion, our findings suggest a novel role for CD36 as essential mediator of proximal tubular apoptosis in human DNP. As glucose induced CD36 expression in PTECs, and since increased CD36 mediated AGE-BSA and/or FFA induced PTEC apoptosis, we propose a new two-step metabolic hit model for TED, a hallmark of progression of human diabetic nephropathy.

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Genes
Symbol Description Cd36 CD36 antigen Mapk14 mitogen activated protein kinase 14 Scarb1 scavenger receptor class B, member 1