Showing papers by "Maria Dolores Sanchez-Niño published in 2009"

The MIF Receptor CD74 in Diabetic Podocyte Injury

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.

Tweak induces proliferation in renal tubular epithelium: a role in uninephrectomy induced renal hyperplasia

Abstract: The tumour necrosis factor (TNF) family member TWEAK activates the Fn14 receptor and has pro-apoptotic, proliferative and pro-inflammatory actions that depend on the cell type and the microenvironment. We explored the proliferative actions of TWEAK on cultured tubular cells and in vivo on renal tubules. Additionally, we studied the role of TWEAK in compensatory proliferation following unilateral nephrectomy and in an inflammatory model of acute kidney injury (AKI) induced by a folic acid overdose. TWEAK increased the proliferation, cell number and cyclin D1 expression of cultured tubular cells, in vitro. Exposure to serum increased TWEAK and Fn14 expression and the proliferative response to TWEAK. TWEAK activated the mitogen-activated protein kinases ERK and p38, the phosphatidyl-inositol 3-kinase (PI3K)/Akt pathway and NF-κB. TWEAK-induced proliferation was prevented by inhibitors of these protein kinases and by the NF-κB inhibitor parthenolide. TWEAK-induced tubular cell proliferation as assessed by PCNA and cyclin D1 expression in the kidneys of adult healthy mice in vivo. By contrast, TWEAK knock-out mice displayed lower tubular cell proliferation in the remnant kidney following unilateral nephrectomy, a non-inflammatory model. This is consistent with TWEAK-induced proliferation on cultured tubular cells in the absence of inflammatory cytokines. Consistent with our previously published data, in the presence of inflammatory cytokines TWEAK promoted apoptosis, not proliferation, of cultured tubular cells. In this regard, TWEAK knock-out mice with AKI displayed less tubular apoptosis and proliferation, as well as improved renal function. In conclusion, TWEAK actions in tubular cells are context dependent. In a non-inflammatory milieu TWEAK induces proliferation of tubular epithelium. This may be relevant for compensatory renal hyperplasia following nephrectomy.

La transcriptómica ilustra nuevas vías letales en la nefropatía diabética

Abstract: La nefropatia diabetica es la causa mas comun de enfermedad renal cronica terminal. La modulacion terapeutica de la angiotensina II retarda, pero no evita, su progresion. La muerte celular contribuye a la perdida de masa renal en las nefropatias cronicas. Un consorcio europeo empleo la transcriptomica en biopsias renales para identificar nuevos mediadores implicados en la muerte de la celula renal durante la nefropatia diabetica. Un 25% de los genes relacionados con la muerte celular estaban expresados diferencialmente en la nefropatia diabetica. TRAIL y osteoprotegerina fueron los genes mas sobreexpresados, y tambien estaba aumentado CD74. Las celulas tubulares y podocitos expresan TRAIL bajo la regulacion de citocinas proinflamatorias (MIF via CD74, TNF). La hiperglucemia sensibiliza a las celulas renales a la apoptosis inducida por TRAIL, mientras que la osteoprotegerina protege. Estos resultados sugieren que, ademas de la glucemia, la inflamacion y TRAIL pueden ser objetivos terapeuticos en la nefropatia diabetica.