Myo-inositol oxygenase (miox) overexpression drives the progression of renal tubulo-interstitial injury in diabetes
figureposted on 15.04.2020, 23:17 authored by Ada AdminAda Admin, Isha Sharma, Fei Deng, Yingjun Liao, Yashpal S. Kanwar
Conceivably, upregulation of myo-inositol oxygenase (MIOX) is associated with altered cellular redox. Its promoter includes oxidant-response elements, and we also discovered binding sites for XBP-1, a transcription factor of ER stress response. Previous studies indicate that MIOX’s upregulation in acute tubular injury is mediated by oxidant and ER stress. Here, we investigated if hyperglycemia leads to accentuation of oxidant and ER stress, while boosting each other’s activities and thereby augmenting tubulo-interstitial injury/fibrosis. We generated MIOX-overexpressing transgenic (MIOX-TG) and -knockout (MIOX-KO) mice. A diabetic state was induced by streptozotocin administration. Also, MIOX-KO were crossbred with Ins2Akita to generate Ins2Akita/KO mice. MIOX-TG mice had worsening renal functions with kidneys having increased oxidant/ER stress, as reflected by DCF/DHE staining, perturbed NAD/NADH and GSH/GSSG ratios, increased NOX-4 expression, apoptosis and its executionary molecules, accentuation of TGF-signaling, Smads and XBP-1 nuclear translocation, expression of GRP78 and XBP1 (ER stress markers) and accelerated tubulo-interstitial fibrosis. These changes were not seen in MIOX-KO mice. Interestingly, such changes were remarkably reduced in Ins2Akita/KO mice, and likewise in vitro experiments with XBP1-siRNA. These findings suggest that MIOX expression accentuates while its deficiency shields kidneys from tubulo-interstitial injury by dampening oxidant and ER stress, which mutually enhance each other’s activity.