Hepatocyte nuclear factor 4α regulates megalin expression in proximal tubular cells

Persistent proteinuria has been indicated to be a major risk factor for the development of tubulointerstitial damage through a process of proinflammatory molecule expression. Monocyte chemoattractant protein-1 (MCP-1) was shown to contribute to recruitment of immune cells into the renal interstitium in acute and chronic renal diseases. However, the molecular mechanisms by which proteinuria causes MCP-1 expression in proximal tubular cells have not been fully clarified. In this study, we examined whether albumin overload-induced MCP-1 expression was regulated by mitogen-activated protein kinase (MAPK) in mouse proximal tubular (mProx) cells. Exposure of mProx cells to delipidated bovine serum albumin (BSA) induced mRNA and protein expression of MCP-1 in a time- and dose-dependent manner. BSA activated extracellular signal-regulated kinase (ERK1/2) and p38 MAPK. The MEK inhibitor U-0126 partially suppressed BSA-induced MCP-1 expression and MCP-1 promoter/luciferase reporter activity. U-0126 also inhibited an increase in nuclear factor-κB and activator protein-1 DNA-binding activity of MCP-1 promoter by protein overload in mProx cells. In addition, we found that U-0126 inhibited BSA-induced nuclear factor-κB reporter activity and inhibitory protein degradation in mProx cells. In conclusion, these findings indicate that ERK signaling is involved in BSA-induced MCP-1 expression in mProx cells.

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Homocysteine stimulates monocyte chemoattractant protein-1 expression in the kidney via nuclear factor-κB activation

AJP Renal Physiology ◽

10.1152/ajprenal.00331.2007 ◽

2008 ◽

Vol 294 (1) ◽

pp. F236-F244 ◽

Cited By ~ 18

Author(s):

Sun-Young Hwang ◽

Connie W. H. Woo ◽

Kathy K. W. Au-Yeung ◽

Yaw L. Siow ◽

Tong Y. Zhu ◽

...

Keyword(s):

Inflammatory Response ◽

Renal Disease ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Proximal Tubular Cells ◽

Monocyte Chemoattractant Protein 1 ◽

Tubular Cells ◽

Monocyte Chemoattractant ◽

Monocyte Chemoattractant Protein ◽

Proximal Tubular

Hyperhomocysteinemia, or an elevation of blood homocysteine (Hcy) levels, is associated with cardiovascular disorders. Although kidney dysfunction is an important risk factor causing hyperhomocysteinemia, the direct effect of Hcy on the kidney is not well documented. There is a positive association between an elevation of blood Hcy levels and the development of chronic kidney disease. Inflammatory response such as increased chemokine expression has been implicated as one of the mechanisms for renal disease. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine that is involved in the inflammatory response in renal disease. Nuclear factor-κB (NF-κB) plays an important role in upregulation of MCP-1 expression. We investigated the effect of hyperhomocysteinemia on MCP-1 expression and the molecular mechanism underling such an effect in rat kidneys as well as in proximal tubular cells. Hyperhomocysteinemia was induced in rats fed a high-methionine diet for 12 wk. The MCP-1 mRNA expression and MCP-1 protein levels were significantly increased in kidneys isolated from hyperhomocysteinemic rats. The NF-κB activity was significantly increased in the same kidneys. Pretreatment of hyperhomocysteinemic rats with a NF-κB inhibitor abolished hyperhomocysteinemia-induced MCP-1 expression in the kidney. To confirm the causative role of NF-κB activation in MCP-1 expression, human kidney proximal tubular cells were transfected with decoy NF-κB oligodeoxynucleotide to inhibit NF-κB activation. Such a treatment prevented Hcy-induced MCP-1 mRNA expression in tubular cells. Our results suggest that hyperhomocysteinemia stimulates MCP-1 expression in the kidney via NF-κB activation. Such an inflammatory response may contribute to renal injury associated with hyperhomocysteinemia.

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