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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-Ventura^*, Jesus Egido^* and Alberto Ortiz^*

^* Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Fundación Renal Iñigo Alvarez de Toledo, Madrid, Spain; Folkhälsan Institute of Genetics, Folkhälsan Research Center, University of Helsinki, and Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Finland; Center for BioAnalytical Sciences, Dublin City University, Ireland; ^|| Division of Nephrology, Universidad Austral, Valdivia, Chile; ^¶ Academic and Children's Renal Unit, University of Bristol, Bristol, United Kingdom; **Department of Medicine, St. Vincent's Hospital, University of Melbourne, Victoria, Australia; Division of Nephrology, University of Michigan, Ann Arbor, Michigan; Division of Nephrology, Childrens Hospital Los Angeles, Los Angeles, California; Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona; ^|||| Institute of Biomedicine/Pharmacology, University of Helsinki, Finland; and ^¶¶ Fondazione D'Amico per la Ricerca sulle Malattie Renali, Milan, Italy

Correspondence: Dr. Alberto Ortiz, Unidad de Diálisis, Fundación Jiménez Díaz, Avda Reyes Católicos 2, 28040 Madrid, Spain. Phone: +34-915-504940; Fax: +34-915-442636; E-mail: aortiz{at}fjd.es

Received for publication February 15, 2008. Accepted for publication July 16, 2008.

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-, 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.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673