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, α-smooth muscle actin (α-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 α-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 α-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.

Key words

myo-inositol oxygenase - diabetic nephropathy - rats - tubulointerstitial injury - renal tubular epithelial cells

References

• 1 Fioretto P, Mauer M. Histopathology of diabetic nephropathy.  Semin Nephrol. 2007;  27 195-207
• 2 Ninichuk V, Kulkarni O, Clauss S, Anders HJ. Tubular atrophy, interstitial fibrosis, and inflammation in type 2 diabetic db/db mice. An accelerated model of advanced diabetic nephropathy.  Eur J Med Res. 2007;  12 351-355
• 3 Forbes JM, Fukami K, Cooper ME. Diabetic nephropathy: where hemodynamics meets metabolism.  Exp Clin Endocrinol Diabetes. 2007;  115 69-84
• 4 Nangaku M. Mechanisms of tubulointerstitial injury in the kidney: final common pathways to end-stage renal failure.  Intern Med. 2004;  43 9-17
• 5 Gilbert RE, Cooper ME. The tubulointerstitium in progressive diabetic kidney disease: more than an aftermath of glomerular injury?.  Kidney Int. 1999;  56 1627-1637
• 6 Phillips AO, Steadman R. Diabetic nephropathy: the central role of renal proximal tubular cells in tubulointerstitial injury.  Histol Histopathol. 2002;  17 247-252
• 7 Thomas MC, Burns WC, Cooper ME. Tubular changes in early diabetic nephropathy.  Adv Chronic Kidney Dis. 2005;  12 177-186
• 8 Simonson MS. Phenotypic transitions and fibrosis in diabetic nephropathy.  Kidney Int. 2007;  71 846-854
• 9 Lan HY. Tubular epithelial-myofibroblast transdifferentiation mechanisms in proximal tubule cells.  Curr Opin Nephrol Hypertens. 2003;  12 25-29
• 10 Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis.  J Clin Invest. 2003;  112 1776-1784
• 11 Deferrari G, Ravera M, Berruti V. Treatment of diabetic nephropathy in its early stages.  Diabetes Metab Res Rev. 2003;  19 101-114
• 12 Volpini RA, da Silva CG, Costa RS, Coimbra TM. Effect of enalapril and losartan on the events that precede diabetic nephropathy in rats.  Diabetes Metab Res Rev. 2003;  19 43-51
• 13 Huang JS, Chuang LY, Guh JY, Huang YJ, Hsu MS. Antioxidants attenuate high glucose-induced hypertrophic growth in renal tubular epithelial cells.  Am J Physiol Renal Physiol. 2007;  293 F1072-F1082
• 14 García Donaire JA, Ruilope LM. Angiotensin receptor blockade in diabetic renal disease focus on candesartan.  Diabetes Res Clin Pract. 2007;  76 ((Suppl 1)) S22-S30
• 15 Yang Q, Dixit B, Wada J, Tian Y, Wallner EI, Srivastva SK, Kanwar YS. Identification of a renal-specific oxido-reductase in newborn diabetic mice.  Proc Natl Acad Sci USA. 2000;  97 9896-9901
• 16 Arner RJ, Prabhu KS, Krishnan V, Johnson MC, Reddy CC. Expression of myo-inositol oxygenase in tissues susceptible to diabetic complications.  Biochem Biophys Res Commun. 2006;  339 816-820
• 17 Nayak B, Xie P, Akagi S, Yang Q, Sun L, Wada J, Thakur A, Danesh FR, Chugh SS, Kanwar YS. Modulation of renal-specific oxidoreductase/myo-inositol oxygenase by high-glucose ambience.  Proc Natl Acad Sci USA. 2005;  102 17952-17957
• 18 Danesh FR, Wada J, Wallner EI, Sahai A, Srivastava SK, Kanwar YS. Gene regulation of aldose-, aldehyde- and a renal specific oxido reductase (RSOR) in the pathobiology of diabetes mellitus.  Curr Med Chem. 2003;  10 1399-1406
• 19 Lassila M, Seah KK, Allen TJ, Thallas V, Thomas MC, Candido R, Burns WC, Forbes JM, Calkin AC, Cooper ME, Jandeleit-Dahm KA. Accelerated nephropathy in diabetic apolipoprotein E-knockout mouse: role of advanced glycation end products.  J Am Soc Nephrol. 2004;  15 2125-2138
• 20 Burns WC, Twigg SM, Forbes JM, Pete J, Tikellis C, Thallas-Bonke V, Thomas MC, Cooper ME, Kantharidis P. Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition: implications for diabetic renal disease.  J Am Soc Nephrol. 2006;  17 2484-2494
• 21 Lee JH, Yeo WS, Roe JH. Induction of the sufA operon encoding Fe-S assembly proteins by superoxide generators and hydrogen peroxide: involvement of OxyR, IHF and an unidentified oxidant-responsive factor.  Mol Microbiol. 2004;  51 1745-1755

Correspondence