Renal Depletion of Myo-Inositol Is Associated With Its Increased Degradation in Animal Models of Metabolic Disease

Am J Physiol Renal Physiol. 2015 Nov 1;309(9):F755-63. doi: 10.1152/ajprenal.00164.2015. Epub 2015 Aug 26.

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.

Keywords: MIOX; diabetes; hypertension; inositol; insulin resistance; kidney; myo-inositol; obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetic Nephropathies / etiology
  • Diabetic Nephropathies / metabolism
  • Hypertension / complications
  • Hypertension / genetics
  • Hypertension / metabolism*
  • Inositol / deficiency
  • Inositol / metabolism*
  • Inositol Oxygenase / genetics
  • Inositol Oxygenase / metabolism
  • Insulin Resistance
  • Kidney Tubules, Proximal / enzymology
  • Kidney Tubules, Proximal / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Obesity / complications
  • Obesity / genetics
  • Obesity / metabolism*
  • Proteins / genetics
  • Proteins / metabolism
  • Rats, Inbred SHR
  • Rats, Inbred WKY
  • Rats, Wistar
  • Xylulose / genetics
  • Xylulose / metabolism

Substances

  • Proteins
  • Inositol
  • Xylulose
  • Inositol Oxygenase
  • Miox protein, rat