Transcriptional and Post-translational Modulation of myo-Inositol Oxygenase by High Glucose and Related Pathobiological Stresses

Abstract

These findings suggest that phosphorylation of RSOR/MIOX enhances its activity, which is augmented by HG via transcriptional/translational events that are also modulated by diabetes-related pathobiological stresses.Diabetic nephropathy in man is characterized by thickening of basement membranes, mesangial expansion with progression to glomerulosclerosis, tubular atrophy, and interstitial fibrosis, resulting ultimately in renal failure (1-3). A number of mechanisms, involving a complex array of glucose-metabolizing enzymes and various signaling molecules, have been proposed for the pathogenesis of diabetic nephropathy (4 -12). One of the molecules whose homeostasis is well known to be adversely affected in diabetic neuropathy is myo-inositol (MI) 2 (13, 14); however, its pathogenetic role in diabetic nephropathy is unclear. MI is an essential molecule distributed ubiquitously, and it plays a vital role in signal transduction and osmoregulation, the latter process due to MI having been endowed with unique properties as an organic osmolyte or polyol (15, 16). As MI is also responsible for phosphoinositide signaling, it would be critical for cellular activity and is likely to have a high turnover rate, and thus its regular supplementation would be necessary to maintain various normal physiological processes (17, 18). The major sources by which it could be derived include dietary uptake, cyclic turnover from phosphoinositide signaling pathway, and de novo synthesis from glucose (19,20), the latter process confined mainly to kidney, brain, liver, and testis. Overall, it seems that MI homeostasis is maintained by a combination of transport, synthesis, and its catabolism. In diabetes, excessive urinary excretion of MI suggests its deranged homeostasis, which in part may be due to the fact that high extracellular glucose inhibits the cellular uptake of MI by compromising its tubular reabsorption (21,22). On the other hand, high glucose generates excessive intracellular sorbitol via the polyol pathway, which also interferes in the uptake of MI and causes its depletion (15,21,22). Besides sorbitol-induced MI depletion and inhibition of cellular MI uptake, there may be further accentuation of MI deficiency related to its catabolism, which is regulated by an enzyme known as myo-inositol oxygenase (MIOX) (23,24). It catabolizes MI to D-glucuronate, which enters into the pentose phosphate pathway following the interconversion of glucuronate to xylulose (25). Conceivably, this catabolic pathway is extensively utilized by the kidney because

myo-Inositol Oxygenase Overexpression Accentuates Generation of Reactive Oxygen Species and Exacerbates Cellular Injury following High Glucose Ambience

“…4A). Most likely, the generation of H 2 O 2 is mediated through transcriptional mechanisms because the MIOX promoter includes carbohydrate response binding as well as oxidant response elements (29). This increase in the generation of ROS was attributable to being mediated through MIOX because its siRNA could notably decrease DCF fluorescence.…”

“…Later, it was found to be a glycolytic enzyme, MIOX (24), which catabolizes myo-inositol to D-glucuronate via the glucuronate-xylulose (G-X) pathway as originally described in the eye lens (25), whereas it has been proposed to be operative in the kidney as well, and its metabolites enter into the pentose pathway (26,27). Past studies indicate that the promoter region of MIOX includes osmotic, carbohydrate, and oxidant/antioxidant response elements and that its transcription is heavily regulated by organic osmolytes, high glucose ambience, and oxidant stress (20,28,29). Because the oxidant stress or ROS are believed to be common denominators in the pathogenesis of DN, the question that we addressed was whether MIOX also contributes further to the ROS-mediated injury in DN, especially to the proximal cortical tubular compartment.…”

Disruption of Renal Tubular Mitochondrial Quality Control by Myo-Inositol Oxygenase in Diabetic Kidney Disease

“…In addition, cells pretreated with the ROS scavenger N-acetylcysteine (NAC) and then subjected to HG showed similar recovery of mitochondrial integrity and reduced apoptosis. Because MIOX has been shown to induce redox imbalance under HG ambience, 18 this would indicate another conceivable pathway through which MIOX may disrupt mitochondrial quality surveillance. Furthermore, Pink1 has been recently reported to facilitate and enhance the protein-protein interaction between Parkin and Mfn2 on the MOM, which could induce activation of mitophagy.…”

“…MIOX, a tubular enzyme, is upregulated during HG ambience, and its critical involvement in the pathogenesis of DKD has been shown. [15][16][17][18] During hyperglycemia, MIOX induces redox imbalance and mitochondrial dysfunction that could result in tubular oxidative injury and apoptosis. 17,18 In view of this contention, the underlying mechanisms by which MIOX may cause mitochondrial dysfunction and tubular cell injury were delineated.…”

“…15,16 Previously, we had shown that the upregulation of MIOX during hyperglycemia could modulate redox imbalance by transcriptional mechanisms and also, conceivably, induce mitochondrial-dependent apoptosis, which inevitably may lead to tubulointerstitial injury and fibrosis. [16][17][18] With respect to the amelioration of such an injury, D-glucaric acid, an anticancer drug, may serve as a potential pharmacologic inhibitor of MIOX. 19 Interestingly, a derivative of this drug is believed to have a renoprotective effect in DKD by a yet to be defined mechanism.…”