title: myo-Inositol Oxygenase Overexpression Accentuates Generation of Reactive Oxygen Species and Exacerbates Cellular Injury following High Glucose Ambience: A NEW MECHANISM RELEVANT TO THE PATHOGENESIS OF DIABETIC NEPHROPATHY.
abstract: Diabetic nephropathy (DN) is characterized by perturbations in metabolic/cellular signaling pathways with generation of reactive oxygen species (ROS). The ROS are regarded as a common denominator of various pathways, and they inflict injury on renal glomerular cells. Recent studies indicate that tubular pathobiology also plays a role in the progression of DN. However, the mechanism(s) for how high (25 mm) glucose (HG) ambience induces tubular damage remains enigmatic. myo-Inositol oxygenase (MIOX) is a tubular enzyme that catabolizes myo-inositol to d-glucuronate via the glucuronate-xylulose (G-X) pathway. In this study, we demonstrated that G-X pathway enzymes are expressed in the kidney, and MIOX expression/bioactivity was up-regulated under HG ambience in LLC-PK1 cells, a tubular cell line. We further investigated whether MIOX overexpression leads to accentuation of tubulo-interstitial injury, as gauged by some of the parameters relevant to the progression of DN. Under HG ambience, MIOX overexpression accentuated redox imbalance, perturbed NAD(+)/NADH ratios, increased ROS generation, depleted reduced glutathione, reduced GSH/GSSG ratio, and enhanced adaptive changes in the profile of the antioxidant defense system. These changes were also accompanied by mitochondrial dysfunctions, DNA damage and induction of apoptosis, accentuated activity of profibrogenic cytokine, and expression of fibronectin, the latter two being the major hallmarks of DN. These perturbations were largely blocked by various ROS inhibitors (Mito Q, diphenyleneiodonium chloride, and N-acetylcysteine) and MIOX/NOX4 siRNA. In conclusion, this study highlights a novel mechanism where MIOX under HG ambience exacerbates renal injury during the progression of diabetic nephropathy following the generation of excessive ROS via an unexplored G-X pathway.
authors.affiliation: From the Department of Nephrology and Renal Institute, 2nd Xiangya Hospital, Central South University, Changsha, Hunan 410011, China and.
authors.forename: Lin
authors.initials: L
authors.lastname: Sun
authors.affiliation: the Departments of Pathology and Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Dutta
authors.affiliation: the Departments of Pathology and Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
authors.affiliation: the Departments of Pathology and Medicine, Northwestern University, Chicago, Illinois 60611. Electronic address: y-kanwar@northwestern.edu.
authors.forename: Yashpal S
authors.initials: YS
authors.lastname: Kanwar
mesh_terms: D000818:Animals; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005947:Glucose / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism; D050562:Inositol Oxygenase / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D018374:LLC-PK1 Cells; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009243:NAD / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013552:Swine; D015854:Up-Regulation
chemical_list: D017382:Reactive Oxygen Species; D009243:NAD; D006861:Hydrogen Peroxide; D050562:Inositol Oxygenase; D005947:Glucose
keywords: diabetes; diabetic nephropathy; extracellular matrix; kidney; myo-inositol oxygenase (MIOX); reactive oxygen species (ROS)