Induction of hemeoxygenase-1 reduces glomerular injury and apoptosis in diabetic spontaneously hypertensive rats

Am J Physiol Renal Physiol. 2012 Apr 1;302(7):F791-800. doi: 10.1152/ajprenal.00472.2011. Epub 2011 Dec 28.

Abstract

Induction of hemeoxygenase-1 (HO-1) lowers blood pressure and reduces organ damage in hypertensive animal models; however, a potential protective role for HO-1 induction against diabetic-induced glomerular injury remains unclear. We hypothesize that HO-1 induction will protect against diabetes-induced glomerular injury by maintaining glomerular integrity and inhibiting renal apoptosis, inflammation, and oxidative stress. Diabetes was induced with streptozotocin in spontaneously hypertensive rats (SHR) as a model where the coexistence of hypertension and diabetes aggravates the progression of diabetic renal injury. Control and diabetic SHR were randomized to receive vehicle or the HO-1 inducer cobalt protoporphyrin (CoPP). Glomerular albumin permeability was significantly greater in diabetic SHR compared with control, consistent with an increase in apoptosis and decreased glomerular nephrin and α(3)β(1)-integrin protein expression in diabetic SHR. CoPP significantly reduced albumin permeability and apoptosis and restored nephrin and α(3)β(1)-integrin protein expression levels in diabetic SHR. Glomerular injury in diabetic SHR was also associated with increases in NF-κB-induced inflammation and oxidative stress relative to vehicle-treated SHR, and CoPP significantly blunted diabetes-induced increases in glomerular inflammation and oxidative stress in diabetic SHR. These effects were specific to exogenous stimulation of HO-1, since incubation with the HO inhibitor stannous mesoporphyrin alone did not alter glomerular inflammatory markers or oxidative stress yet was able to prevent CoPP-mediated decreases in these parameters. These data suggest that induction of HO-1 reduces diabetic induced-glomerular injury and apoptosis and these effects are associated with decreased NF-κB-induced inflammation and oxidative stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Blood Glucose / metabolism
  • Blood Pressure / drug effects
  • Diabetes Mellitus, Experimental
  • Diabetic Nephropathies / complications
  • Diabetic Nephropathies / enzymology
  • Diabetic Nephropathies / prevention & control*
  • Drug Evaluation, Preclinical
  • Heme Oxygenase-1 / drug effects
  • Heme Oxygenase-1 / metabolism*
  • Hypertension / complications
  • Hypertension / drug therapy*
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Kidney Glomerulus / drug effects
  • Kidney Glomerulus / metabolism
  • Male
  • Nephrosclerosis / etiology
  • Nephrosclerosis / metabolism
  • Oxidative Stress / drug effects
  • Permeability / drug effects
  • Proteinuria / drug therapy
  • Protoporphyrins / pharmacology
  • Protoporphyrins / therapeutic use*
  • Random Allocation
  • Rats
  • Rats, Inbred SHR

Substances

  • Blood Glucose
  • Protoporphyrins
  • cobaltiprotoporphyrin
  • Heme Oxygenase-1