Increased Expression of Myo-inositol Oxygenase is Involved in the Tubulointerstitial Injury of Diabetic Nephropathy

Abstract

Myo-inositol oxygenase (MIOX) catalyzes the oxidative cleavage of myo-inositol (MI) to give D-glucuronic acid, a committed step in MI catabolism. Previous studies have shown that increased mRNA and protein levels of MIOX in the cortex of the kidney in diabetic mice. The implication of MIOX expression in diabetic nephropathy, however, has not been revealed. In the present study, we demonstrate for the first time that the expression of MIOX was increased at both the mRNA and protein levels in the kidney of rats with diabetic nephropathy. In addition, alpha-smooth muscle actin (alpha-SMA) and fibronectin levels were increased and E-cadherin levels decreased in the same diabetic kidneys. In vitro, studies have shown that high concentrations of glucose significantly increased MIOX secretion in rat renal tubular epithelial cells NRK-52E in a dose-dependent manner, suggesting that hyperglycemia is a direct cause of the MIOX increase in the kidney. With respect to the function of MIOX, we have shown that overexpression of MIOX induces greater levels of alpha-SMA, increased fibronectin expression, and lower levels of E-cadherin expression relative to normal NRK-52E cells. The blockade of MIOX by antisense oligonucleotide (ODN) inhibits high glucose-induced production of alpha-SMA and fibronectin in normal NRK-52E cells. This suggests that increased expression of MIOX in diabetic kidneys may contribute to tubulointerstitial injury and the development of diabetic nephropathy.