Induction of hemeoxygenase-1 reduces glomerular injury and apoptosis in diabetic spontaneously hypertensive rats.
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.
Georgia Health Sciences University, Augusta, GA 30912, USA. aelmarakby@georgiahealth.edu
Ahmed A
AA
Elmarakby
Jessica
J
Faulkner
Babak
B
Baban
Mohamed A
MA
Saleh
Jennifer C
JC
Sullivan
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental; D003928:Diabetic Nephropathies / Q000150:complications / Q000201:enzymology / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical; D051547:Heme Oxygenase-1 / Q000187:drug effects / Q000378:metabolism*; D006973:Hypertension / Q000150:complications / Q000188:drug therapy*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009400:Nephrosclerosis / Q000209:etiology / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010539:Permeability / Q000187:drug effects; D011507:Proteinuria / Q000188:drug therapy; D011524:Protoporphyrins / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR
D001786:Blood Glucose; D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; D051547:Heme Oxygenase-1