The MIF receptor CD74 in diabetic podocyte injury.
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-alpha, 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.
Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Fundación Renal Iñigo Alvarez de Toledo, Madrid, Spain.
Maria Dolores
MD
Sanchez-Niño
Ana Belen
AB
Sanz
Pekka
P
Ihalmo
Markus
M
Lassila
Harry
H
Holthofer
Sergio
S
Mezzano
Claudio
C
Aros
Per-Henrik
PH
Groop
Moin A
MA
Saleem
Peter W
PW
Mathieson
Robert
R
Langham
Matthias
M
Kretzler
Viji
V
Nair
Kevin V
KV
Lemley
Robert G
RG
Nelson
Eero
E
Mervaala
Deborah
D
Mattinzoli
Maria Pia
MP
Rastaldi
Marta
M
Ruiz-Ortega
Jose Luis
JL
Martin-Ventura
Jesus
J
Egido
Alberto
A
Ortiz
D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D001706:Biopsy; D018932:Chemokine CCL2 / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism*; D005786:Gene Expression Regulation; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007249:Inflammation; D007684:Kidney Tubules / Q000378:metabolism; D020935:MAP Kinase Signaling System; D050199:Podocytes / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000944:Antigens, Differentiation, B-Lymphocyte; D018932:Chemokine CCL2; D000949:Histocompatibility Antigens Class II; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; C045084:invariant chain; D048051:p38 Mitogen-Activated Protein Kinases