DB19-0935R2 Supplemental File.docx (2.56 MB)
Myo-inositol oxygenase (miox) overexpression drives the progression of renal tubulo-interstitial injury in diabetes
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posted on 2020-04-15, 23:17 authored by Ada AdminAda Admin, Isha Sharma, Fei Deng, Yingjun Liao, Yashpal S. KanwarConceivably, 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.