Identification of a novel kidney-specific gene downregulated in acute ischemic renal failure

Hu, Erding; Chen, Zunxuan; Fredrickson, Todd A.; Gellai, Miklos; Jugus, M; Contino, Lisa C.; Spurr, Nigel K.; Sims, Matthew; Halsey, Wendy S.; Horn, Stephanie Van; Mao, Joyce; Sathe, Ganesh M.; Brooks, David P.

doi:10.1152/ajprenal.2000.279.3.f426

Cited by 14 publications

(13 citation statements)

References 30 publications

(25 reference statements)

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“…Previous studies from many laboratories, including ours (2,(22)(23)(24)(25), have reported that MIOX occurs predominantly in the cortical region of the kidney. In the cortex, proximal tubule epithelial cells are responsible for the uptake of the majority of water and nearly all metabolites from the filtrate.…”

Section: Discussionmentioning

confidence: 68%

Up-regulation of Human myo-Inositol Oxygenase by Hyperosmotic Stress in Renal Proximal Tubular Epithelial Cells

Prabhu

Arner

Vunta

et al. 2005

Journal of Biological Chemistry

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myo-Inositol oxygenase (MIOX) catalyzes the oxidative cleavage of myo-inositol (MI) to give D-glucuronic acid, a committed step in MI catabolism. D-Glucuronic acid is further metabolized to xylitol via the glucuronate-xylulose pathway. Although accumulation of polyols such as xylitol and sorbitol is associated with MI depletion in diabetic complications, no causal relationship has been established. Therefore we are examining the role of MIOX in diabetic nephropathy. Here we present evidence that the basis for the depletion of MI in diabetes is likely to be mediated by the increased expression of MIOX, which is induced by sorbitol, mannitol, and xylitol in a porcine renal proximal tubular epithelial cell line, LLC-PK1. To understand the molecular mechanism of regulation of MIOX expression by polyols, we have cloned the human MIOX gene locus of 10 kb containing 5.6 kb of the 5 upstream sequence. Analysis of the 5 upstream sequence led to the identification of an osmotic response element (ORE) in the promoter region, which is present ϳ2 kb upstream of the translation start site. Based on luciferase reporter and electrophoretic mobility shift assays, polyols increased the ORE-dependent expression of MIOX. In addition, we demonstrate that the activity of the promoter is dependent on the binding of the transcription factor, tonicity element-binding protein, or osmotic response elementbinding protein, to the ORE site. These results suggest that the expression of MIOX is up-regulated by a positive feedback mechanism where xylitol, one of the products of MI catabolism via the glucuronate-xylulose pathway, induces an overexpression of MIOX. myo-Inositol (MI),1 the dominant form of the physiological inositol isomers, is utilized in many tissues and cell types as a precursor for the synthesis of second messengers and also as an organic osmolyte (1). The first committed step in MI metabolism is catalyzed by the monooxygenase, myo-inositol oxygenase (MIOX; EC 1.13.99.1), which occurs predominantly in the proximal tubular epithelial cells of the kidney cortex (2). The enzymatic reaction involves the oxidative cleavage of the ring in MI between C-6 and C-1 to give D-glucuronic acid. The D-glucuronate formed in animals by this mechanism is successively converted in subsequent steps to L-gluonate, 3-keto-L-gulonate, L-xylulose, xylitol, D-xylulose, and D-xylulose 5-phosphate, which then enters the pentose phosphate cycle (Fig. 1). Studies in human pentosuric patients confirmed that this is the only pathway of MI catabolism (3). We have recently reported the cloning and expression of MIOX, where we demonstrated that D-chiro-inositol, a MI isomer that exhibits insulin-like signaling properties (4), is also a substrate for MIOX (2).myo-Inositol has been suggested to play an important role in the etiology of diabetes mellitus, particularly with respect to the progression of diabetic nephropathy, neuropathy, retinopathy, and diabetic cataract. In diabetic complications, increased glucose levels are associated with high sorbitol accumu...

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Section: Discussionmentioning

confidence: 68%

Up-regulation of Human myo-Inositol Oxygenase by Hyperosmotic Stress in Renal Proximal Tubular Epithelial Cells

Prabhu

Arner

Vunta

et al. 2005

Journal of Biological Chemistry

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“…8I) would corroborate the data of D-glucoseinduced up-regulation of RSOR͞MIOX. Here, it is worth pointing out a potential paradox that a decreased RSOR͞MIOX expression has been reported in acute renal failure (39), where tubular cells are under extreme oxidant stress (40). It may be that expression of the enzyme depends on the degree or type of oxidant stress (cytosolic vs. membrane vs. mitochondrial); nevertheless, it seems that OxREs are functionally active in RSOR͞MIOX promoter.…”

Section: Discussionmentioning

confidence: 96%

“…The MI has a dynamic role for membrane phosphoinositides in providing for the release of second messengers, such as 1,2 diacylglycerol and inositol triphosphate; therefore, the RSOR, normally expressed in the cortex, conceivably modulates phosphoinositide signaling critical for various cellular events of the renal tubular epithelium. Another recently described gene, designated as kidney-specific protein-32 (KSP32), is also homologous to RSOR (22). The KSR-32 gene was discovered serendipitously in rats with acute renal failure.…”

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confidence: 99%

Modulation of renal-specific oxidoreductase/ myo -inositol oxygenase by high-glucose ambience

Nayak¹,

Xie²,

Akagi³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Biological properties of renal-specific oxidoreductase (RSOR), characteristics of its promoter, and underlying mechanisms regulating its expression in diabetes were analyzed. RSOR expression, normally confined to the renal cortex, was markedly increased and extended into the outer medullary tubules in db͞db mice, a model of type 2 diabetes. Exposure of LLCPK cells to D-glucose resulted in a dose-dependent increase in RSOR expression and its enzymatic activity. The latter was related to one of the glycolytic enzymes, myo-inositol oxygenase. The increase in activity was in proportion to serum glucose concentration. The RSOR expression also increased in cells treated with various organic osmolytes, e.g., sorbitol, myoinositol, and glycerolphosphoryl-choline and H 2O2. Basal promoter activity was confined to ؊1,252 bp upstream of ATG, and it increased with the treatment of high glucose and osmolytes. EMSAs indicated an increased binding activity with osmotic-, carbohydrate-, and oxidant-response elements in cells treated with high glucose and was abolished by competitors. Supershifts, detected by anti-nuclear factor of activated T cells, and carbohydrate-response-element-binding protein established the binding specificity. Nuclear factor of activated T cells tonicityenhancer-binding protein and carbohydrate-response-elementbinding protein had increased nuclear expression in cells treated with high glucose. The activity of osmotic-response element exhibited a unique alternate binding pattern, as yet unreported in osmoregulatory genes. Data indicate that RSOR activity is modulated by diverse mechanisms, and it is endowed with dual properties to channel glucose intermediaries, characteristic of hepatic aldehyde reductases, and to maintain osmoregulation, a function of renal medullary genes, e.g., aldose reductase, in diabetes. diabetic nephropathy ͉ hyperglycemia ͉ osmoregulation D iabetic nephropathy is characterized by hyperplasia͞ hypertrophy of intrinsic renal cells and increased extracellular matrices (1). These changes are related to the increased cellular flux of glucose intermediaries (2), de novo synthesis of intra-and extracellular advanced glycation end products (3, 4), activation of protein kinase C (5, 6), increased expression of transforming growth factor-␤ (7), increased activity of GTP-binding and cell-cycle proteins (6,8), and generation of reactive oxygen species (9, 10), with consequential compromise in renal functions (11,12). Such complex interrelated cellular signaling events, also involving various forms of MAP͞ERK kinases and Smad proteins, have been defined mainly in glomerular cells (13,14); information relevant to the tubulointerstitial cells, although notably affected, is limited (15, 16). Conceivably, cellular changes in the tubulointerstitium parallel those in the glomerulus, with scarring and thickening of the basement membranes, and they correlate relatively better with the derangements in renal functional parameters (17, 18). Thus, much attention is warranted to the understanding of the...

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“…MIOX is a 32-kDa protein, which was originally identified as mouse renal-specific oxidoreductase (RSOR), has affinity for NADPH, and is also known as kidney-specific protein 32 (KSP-32) (23,29). MIOX expression is up-regulated in diabetes mellitus (23,28), and conceivably, its up-regulation may be responsible for the concomitant MI depletion and increased urinary excretion.…”

mentioning

confidence: 99%

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

Nayak

Kondeti

Xie

et al. 2011

Journal of Biological Chemistry

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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

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Identification of a novel kidney-specific gene downregulated in acute ischemic renal failure

Cited by 14 publications

References 30 publications

Up-regulation of Human myo-Inositol Oxygenase by Hyperosmotic Stress in Renal Proximal Tubular Epithelial Cells

Up-regulation of Human myo-Inositol Oxygenase by Hyperosmotic Stress in Renal Proximal Tubular Epithelial Cells

Modulation of renal-specific oxidoreductase/ myo -inositol oxygenase by high-glucose ambience

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

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