Abstract
The renoprotective mechanisms of hemeoxygenase-1 (HO-1) in diabetic nephropathy remain to be investigated. We hypothesize that HO-1 protects the kidney from diabetic insult via lowering renal oxidative stress and inflammation. We used control and diabetic SHR with or without HO-1 inducer cobalt protoporphyrin (CoPP) treatment for 6 weeks. Urinary albumin excretion levels were significantly elevated in diabetic SHR compared to control and CoPP significantly attenuated albumin excretion. Immuno-histochemical analysis revealed an elevation in TGF-β staining together with increased urinary collagen excretion in diabetic versus control SHR, both of which were reduced with CoPP treatment. Renal oxidative stress markers were greater in diabetic SHR and reduced with CoPP treatment. The increase in renal oxidative stress was associated with an elevation in renal inflammation in diabetic SHR. CoPP treatment also significantly attenuated the markers of renal inflammation in diabetic SHR. In vitro inhibition of HO with stannous mesoporphyrin (SnMP) increased glomerular NADPH oxidase activity and inflammation and blocked the anti-oxidant and anti-inflammatory effects of CoPP. These data suggest that the reduction of renal injury in diabetic SHR upon induction of HO-1 are associated with decreased renal oxidative stress and inflammation, implicating the role of HO-1 induction as a future treatment of diabetic nephropathy.
Highlights
The incidence of diabetes mellitus has dramatically increased worldwide [1, 2]
cobalt protoporphyrin (CoPP) treatment reduced blood pressure (187 ± 2 mmHg) and blood glucose (425 ± 47 mg/dL) in diabetic spontaneously hypertensive rats (SHR); blood glucose and blood pressure remained significantly higher than control SHR
The current study provides evidence that HO-1 induction mitigates renal injury and inflammation in type 1 diabetic SHR as a model in which diabetes coexists with hypertension to exaggerate the progression of renal injury
Summary
The incidence of diabetes mellitus has dramatically increased worldwide [1, 2]. One of the major complications of diabetes is the progression of renal injury, affecting approximately 35% of type 1 and type 2 diabetic patients, which often leads to end-stage renal disease. NADPH oxidase has been shown to be activated in the kidney of diabetic animal models, with enhanced expression in the glomerulus and distal tubules [9,10,11]. NADPH oxidase-derived reactive oxygen species increase renal hypertrophy and fibronectin expression in streptozotocin-induced type 1 diabetic rats [11, 12] as well as exacerbate the damage in glomerular basement membrane and slit diaphragm [10, 13]. These data suggest that NADPH oxidase-derived superoxide contributes to the progression of diabetic-induced renal injury
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