title: Renal depletion of myo-inositol is associated with its increased degradation in animal models of metabolic disease.
abstract: Renal depletion of myo-inositol (MI) is associated with the pathogenesis of diabetic nephropathy in animal models, but the underlying mechanisms involved are unclear. We hypothesized that MI depletion was due to changes in inositol metabolism and therefore examined the expression of genes regulating de novo biosynthesis, reabsorption, and catabolism of MI. We also extended the analyses from diabetes mellitus to animal models of dietary-induced obesity and hypertension. We found that renal MI depletion was pervasive across these three distinct disease states in the relative order: hypertension (-51%)>diabetes mellitus (-35%)>dietary-induced obesity (-19%). In 4-wk diabetic kidneys and in kidneys derived from insulin-resistant and hypertensive rats, MI depletion was correlated with activity of the MI-degrading enzyme myo-inositol oxygenase (MIOX). By contrast, there was decreased MIOX expression in 8-wk diabetic kidneys. Immunohistochemistry localized the MI-degrading pathway comprising MIOX and the glucuronate-xylulose (GX) pathway to the proximal tubules within the renal cortex. These findings indicate that MI depletion could reflect increased catabolism through MIOX and the GX pathway and implicate a common pathological mechanism contributing to renal oxidative stress in metabolic disease.
authors: School of Biological Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
authors: H-H
authors: HH
authors: Chang
authors: School of Biological Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
authors: H-N
authors: HN
authors: Chao
authors: School of Biological Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
authors: C S
authors: CS
authors: Walker
authors: School of Biological Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
authors: S-Y
authors: SY
authors: Choong
authors: School of Biological Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
authors: A
authors: A
authors: Phillips
authors: School of Biological Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand k.loomes@auckland.ac.nz.
authors: K M
authors: KM
authors: Loomes
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism; D006973:Hypertension / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D007294:Inositol / Q000172:deficiency / Q000378:metabolism*; D050562:Inositol Oxygenase / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D007687:Kidney Tubules, Proximal / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017208:Rats, Wistar; D014996:Xylulose / Q000235:genetics / Q000378:metabolism
chemical_list: D011506:Proteins; D007294:Inositol; D014996:Xylulose; D050562:Inositol Oxygenase; C414007:Miox protein, rat
keywords: MIOX; diabetes; hypertension; inositol; insulin resistance; kidney; myo-inositol; obesity