The MIF receptor CD74 in diabetic podocyte injury

Maria Dolores Sanchez-Niño, Ana Belen Sanz, Pekka Ihalmo, Markus Lassila, Harry Holthofer, Sergio Mezzano, Claudio Aros, Per Henrik Groop, Moin A Saleem, Peter W Mathieson, Robert Langham, Matthias Kretzler, Viji Nair, Kevin V Lemley, Robert G. Nelson, Eero Mervaala, Deborah Mattinzoli, Maria Pia Rastaldi, Marta Ruiz-Ortega, Jose Luis Martin-VenturaJesus Egidoalberto Ortiz

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Abstract

Although metabolic derangement plays a central role in diabetic nephropathy, a better understanding of secondary mediators of injury may lead to new therapeutic strategies. Expression of macrophage migration inhibitory factor (MIF) is increased in experimental diabetic nephropathy, and increased tubulointerstitial mRNA expression of its receptor, CD74, has been observed in human diabetic nephropathy. Whether CD74 transduces MIF signals in podocytes, however, is unknown. Here, we found glomerular and tubulointerstitial CD74 mRNA expression to be increased in Pima Indians with type 2 diabetes and diabetic nephropathy. Immunohistochemistry confirmed the increased glomerular and tubular expression of CD74 in clinical and experimental diabetic nephropathy and localized glomerular CD74 to podocytes. In cultured human podocytes, CD74 was expressed at the cell surface, was upregulated by high concentrations of glucose and TNF-α, and was activated by MIF, leading to phosphorylation of extracellular signal-regulated kinase 1/2 and p38. High glucose also induced CD74 expression in a human proximal tubule cell line (HK2). In addition, MIF induced the expression of the inflammatory mediators TRAIL and monocyte chemoattractant protein 1 in podocytes and HK2 cells in a p38-dependent manner. These data suggest that CD74 acts as a receptor for MIF in podocytes and may play a role in the pathogenesis of diabetic nephropathy.

Original languageEnglish
Pages (from-to)353-362
Number of pages10
JournalJournal of the American Society of Nephrology
Volume20
Issue number2
DOIs
Publication statusPublished - Feb 2009
Externally publishedYes

Cite this

Sanchez-Niño, M. D., Sanz, A. B., Ihalmo, P., Lassila, M., Holthofer, H., Mezzano, S., Aros, C., Groop, P. H., Saleem, M. A., Mathieson, P. W., Langham, R., Kretzler, M., Nair, V., Lemley, K. V., Nelson, R. G., Mervaala, E., Mattinzoli, D., Rastaldi, M. P., Ruiz-Ortega, M., ... Ortiz, J. E. (2009). The MIF receptor CD74 in diabetic podocyte injury. Journal of the American Society of Nephrology, 20(2), 353-362. https://doi.org/10.1681/ASN.2008020194