title: Combination therapy with spironolactone and candesartan protects against streptozotocin-induced diabetic nephropathy in rats.
abstract: Diabetic nephropathy is one of the most common causes of end-stage kidney disease. Aldosterone and angiotensin II appear to play a crucial role in the pathogenesis of this disease. The present study aimed to investigate effects of the combination therapy with spironolactone and candesartan on diabetic nephropathy and elucidate the underlying mechanism(s) involved. Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin (STZ) (55 mg/kg). The diabetic rats were orally treated with spironolactone (50 mg/kg/day) and/or candesartan (1 mg/kg/day) for 8 weeks. Administration of STZ caused a marked elevation in the serum level of creatinine, urea and urinary albumin-creatinine ratio (ACR). This was associated with upregulated renal protein levels of nuclear factor-kappa B (NF-κB), transforming growth factor (TGF)-β, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) alongside increasing the renal superoxide anion (O2(-)) production, malondialdehyde (MDA) level and the systolic blood pressure. There was a marked decrease in nitric oxide (NO) bioavailability and antioxidant enzyme capacity. The combined therapy of spironolactone and candesartan significantly normalized the oxidative stress and fibrotic/inflammatory alterations. Additionally, the elevated blood pressure was attenuated by administration of candesartan alone or in combination. This was associated with improving the renal function parameters. The combined therapy exhibited more profound response compared to the monotherapy. In conclusion, our results demonstrate that the combined therapy of spironolactone and candesartan can confer an additive benefit over the use of either drug alone against STZ-induced diabetic nephropathy, presumably via attenuating the inflammatory responses and oxidative status markers.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, 61511 Minia, Egypt. Electronic address: amal_arwa1@yahoo.com.
authors.forename: Amal
authors.initials: A
authors.lastname: Hofni
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, 61511 Minia, Egypt; Department of Pharmacology and Toxicology, Ibn Sina National College for Medical Studies, Jeddah, Saudi Arabia.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: El-Moselhy
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, 61511 Minia, Egypt.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Taye
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, 61511 Minia, Egypt.
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Khalifa
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D004359:Drug Therapy, Combination / Q000379:methods; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013148:Spironolactone / Q000494:pharmacology*; D013311:Streptozocin / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000975:Antioxidants; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D016328:NF-kappa B; D020011:Protective Agents; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D013481:Superoxides; D013148:Spironolactone; D009569:Nitric Oxide; D008315:Malondialdehyde; D013311:Streptozocin; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; C081643:candesartan
keywords: Candesartan; Diabetic nephropathy; Oxidative stress; Spironolactone