title: Amelioration of experimentally induced diabetic nephropathy and renal damage by nilotinib.
abstract: Diabetes mellitus is an ever growing world-wide health problem. The patient has to stick to a firm life-long therapeutic regimen, otherwise diabetic complications will develop. Diabetic nephropathy (DN) is one of the most common diabetic complications and it requires careful medical attendance. Nilotinib hydrochloride is a protein tyrosine kinase inhibitor reported to have numerous therapeutic efficacies besides being an anticancer. In the current study, single I.P. streptozotocin (50 mg/kg) injection was used to induce type I diabetes mellitus in male Sprague-Dawley rats. After 8 weeks, significant deterioration of renal function with urinary excretion of nephrin, podocalyxin, and albumin was observed. Daily oral administration of nilotinib (20 mg/kg) for 8 weeks significantly improved signs of DN on all investigated scales. On a biochemical scale, kidney functions, albuminuria, urinary nephrin, podocalyxin excretion, and host oxidant/antioxidant balance significantly improved. Kidney content of nitric oxide, expression of toll-like receptors 4 and NF-κB/p65 activity significantly declined as well. On a histopathological scale, α-smooth muscle actin and nestin expression significantly declined. Meanwhile, area of fibrosis significantly declined as seen with significant reduction in accumulation of extracellular matrix components and kidney content of collagen. Ultimately, such improvements were accompanied by significant restoration of normal kidney physiology and function. In conclusion, nilotinib can hinder progression of DN through various mechanisms. Reduction of oxidative stress, enhancement of host antioxidant defense system, reduction of inflammation, angiogenesis, tissue hypoxia, and pro-fibrogenic biomarker expression can be implicated in the beneficial therapeutic outcome observed with nilotinib therapy.
authors: Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
authors: Nehal Mohsen
authors: NM
authors: Elsherbiny
authors: Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
authors: Mohamed
authors: M
authors: El-Sherbiny
authors: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, 35516, Mansoura, Egypt. emansaid@mans.edu.eg.
authors: Eman
authors: E
authors: Said
mesh_terms: D000818:Animals; D001806:Blood Urea Nitrogen; D003094:Collagen / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D005978:Glutathione / Q000378:metabolism; D006909:Hydroxyproline / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D018384:Oxidative Stress; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C498145:Rela protein, rat; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D008315:Malondialdehyde; D003094:Collagen; D003404:Creatinine; D013482:Superoxide Dismutase; C498826:nilotinib; D005978:Glutathione; D006909:Hydroxyproline
keywords: Diabetic nephropathy; NFκβ/p65 activity; Nestin; Nilotinib; Toll-like receptors 4; α-Smooth muscle actin