Effect of pioglitazone on the early stage of type 2 diabetic nephropathy in KK/Ta mice

Metabolism. 2004 Nov;53(11):1473-9. doi: 10.1016/j.metabol.2004.06.016.


Pioglitazone (PIO) has preventive effects on impaired glucose tolerance (IGT) and urinary albumin excretion in diabetes. These effects in the early stage of diabetic nephropathy have not been fully described. Endothelial constitutive nitric oxide synthase (ecNOS) might be one of the mechanisms of glomerular hyperfiltration. The objective of the present study was to evaluate the effect of PIO, including the role of ecNOS on the early stage of diabetic nephropathy in KK/Ta mice. KK/Ta mice were given PIO (10 mg/kg/d) started at 12 or 16 weeks of age for 8 or 4 weeks, respectively. They were divided into 3 groups as follows: early treatment (n = 8), late treatment (n = 8), and control group (n = 12). The urinary albumin/creatinine ratio (ACR), fasting and casual blood glucose levels, ratio of glomerular and Bowman's capsule volume (GB ratio), and systemic blood pressure were measured as phenotypic characterizations. The ecNOS and iNOS protein expression in glomeruli were evaluated by immunofluorescence. PIO, especially early treatment, improved the ACR and the GB ratio, and ecNOS protein expression was decreased in the endothelium of glomerular vessels. The iNOS protein was not detectable. There were no significant changes in the levels of fasting and casual blood glucose and systemic blood pressure among all groups. We conclude that the effect of PIO on microalbuminuria might not be due to changing systemic blood pressure and blood glucose levels. It appears that the decrease of urinary albumin excretion might be related to improvement of glomerular enlargement, including hyperfiltration, since the levels of ecNOS protein were reduced by PIO in the glomerular vessels.

MeSH terms

  • Albuminuria / etiology
  • Albuminuria / prevention & control
  • Animals
  • Blood Glucose / metabolism
  • Blood Pressure
  • Creatinine / blood
  • Diabetes Mellitus, Type 2 / complications*
  • Diabetic Nephropathies / blood
  • Diabetic Nephropathies / complications
  • Diabetic Nephropathies / enzymology
  • Diabetic Nephropathies / etiology
  • Diabetic Nephropathies / physiopathology*
  • Drug Administration Schedule
  • Fluorescent Antibody Technique
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / pharmacology*
  • Kidney Glomerulus / enzymology
  • Kidney Glomerulus / metabolism*
  • Male
  • Mice
  • Mice, Inbred Strains
  • Nitric Oxide Synthase / metabolism*
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Phenotype
  • Pioglitazone
  • Serum Albumin / metabolism
  • Thiazolidinediones / administration & dosage
  • Thiazolidinediones / pharmacology*


  • Blood Glucose
  • Hypoglycemic Agents
  • Serum Albumin
  • Thiazolidinediones
  • Creatinine
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Nos2 protein, mouse
  • Nos3 protein, mouse
  • Pioglitazone