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Modulation of heme oxygenase‐1 expression and activity affects streptozotocin‐induced diabetic nephropathy in rats
Author(s) -
Ali Marwa A.M.,
Heeba Gehan H.,
ElSheikh Azza A.K.
Publication year - 2017
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/fcp.12296
Subject(s) - heme oxygenase , endocrinology , medicine , streptozotocin , diabetic nephropathy , malondialdehyde , kidney , oxidative stress , chemistry , renal function , superoxide dismutase , nephropathy , zinc protoporphyrin , heme , diabetes mellitus , biochemistry , enzyme
Heme oxygenase ( HO )‐1 has exhibited nephro‐protective actions in different animal models; however, its full mechanistic potential in diabetic nephropathy ( DN ) has not yet been elucidated. Hence, the present study has been undertaken by inducing DN in rats using streptozotocin (50 mg/kg i.p.), with or without either HO ‐1 inducer; hemin ( HM ; 40 μmol/kg, s.c.), or HO ‐1 blocker; zinc protoporphyrin‐ IX (Zn PP ; 50 μmol/kg, i.p.), for one month. Compared to control, rats with DN suffered from hyperglycemia and hyperlipidemia, with signs of renal damage, as assessed by distortion in renal histopathologic architecture and kidney function. Renal oxidative/nitrosative stress was evident by increased malondialdehyde, nitric oxide, myeloperoxidase, with decreased reduced glutathione, superoxide dismutase, and catalase. DN group also exhibited high renal expression of the pro‐inflammatory cytokine; tumor necrosis factor ( TNF )‐α, and the apoptotic marker; caspase 3, assessed by Western blot. Renal HO ‐1 protein expression and activity were increased in DN rats compared to control. Administration of HM , but not Zn PP , to DN rats improved kidney function, histopathologic features, lipid profile, TNF ‐α, and caspase 3 expressions, with no effect on blood glucose level. HM increased, while Zn PP decreased renal HO ‐1 activity in DN rats. It is noteworthy that neither intervention affected HO ‐1 activity or renal oxidative capacity in non‐diabetic rats. Interestingly, the expression of HO ‐1 was upregulated by both HM and Zn PP in DN rats. In conclusion, activation of HO ‐1 via HM ameliorated renal damage in STZ ‐induced DN in rats, probably through antioxidant, anti‐nitrosative, anti‐inflammatory, and anti‐apoptotic mechanisms.