<i>Myo</i>-inositol Oxygenase (MIOX) Overexpression Drives the Progression of Renal Tubulointerstitial Injury in Diabetes.

Abstract

Conceivably, upregulation of <i>myo</i>-inositol oxygenase (MIOX) is associated with altered cellular redox. Its promoter includes oxidant-response elements, and we also discovered binding sites for XBP1, a transcription factor of endoplasmic reticulum (ER) stress response. Previous studies indicate that MIOX's upregulation in acute tubular injury is mediated by oxidant and ER stress. Here, we investigated whether hyperglycemia leads to accentuation of oxidant and ER stress while these boost each other's activities, thereby augmenting tubulointerstitial injury/fibrosis. We generated MIOX-overexpressing transgenic (MIOX-TG) and MIOX knockout (MIOX-KO) mice. A diabetic state was induced by streptozotocin administration. Also, MIOX-KO were crossbred with <i>Ins2</i> ^Akit<i>a</i> to generate <i>Ins2</i> ^Akita/KO mice. MIOX-TG mice had worsening renal functions with kidneys having increased oxidant/ER stress, as reflected by DCF/dihydroethidium staining, perturbed NAD-to-NADH and glutathione-to-glutathione disulfide ratios, increased NOX4 expression, apoptosis and its executionary molecules, accentuation of TGF-β signaling, Smads and XBP1 nuclear translocation, expression of GRP78 and XBP1 (ER stress markers), and accelerated tubulointerstitial fibrosis. These changes were not seen in MIOX-KO mice. Interestingly, such changes were remarkably reduced in <i>Ins2</i> ^Akita/KO mice and, likewise, in vitro experiments with XBP1 siRNA. These findings suggest that MIOX expression accentuates, while its deficiency shields kidneys from, tubulointerstitial injury by dampening oxidant and ER stress, which mutually enhance each other's activity.