title: Role for NF-κB inflammatory signalling pathway in tenofovir disoproxil fumarate (TDF) induced renal damage in rats.
abstract: Nephrotoxicity due to tenofovir treatment of HIV patients has been reported. However, the mechanism of tenofovir nephrotoxicity is not clear. NFκB is an important proinflammatory transcription factor that plays a pivotal role in oxidative stress-induced inflammation. We hypothesized that NFκB proinflammatory signalling pathway may play a role in tenofovir induced renal damage. Renal damage was induced in adult male Wistar rats by the oral administration of 600 mg/kg body wt. daily for 5 consecutive weeks. Kidneys were removed and used for histological and biochemical analysis. The protein and mRNA expressions of NFκB and its target genes namely iNOS, COX-2 and TNFα, and its inhibitor IκB-alpha were analysed by immunohistochemical methods, western blot and quantitative RT PCR. NFκBp65 activity was determined by ELISA. The protein and mRNA expressions of NFκB p65, iNOS, COX-2 and TNFα were increased in the kidneys of TDF treated rats. The activity of NFκBp65 was increased by 28 fold in the nuclear fractions of the TDF treated rat kidneys. Pretreatment with melatonin, a NFκB inhibitor attenuated TDF induced renal damage. It is concluded that the activation of NFκB and its downstream proinflammatory target genes iNOS, COX-2, and TNF-α may contribute to the pathophysiology of TDF induced renal damage.
authors.affiliation: Department of Biochemistry, Christian Medical College, Bagayam, Vellore 632002, Tamil Nadu, India.
authors.forename: Hemalatha
authors.initials: H
authors.lastname: Ramamoorthy
authors.affiliation: Department of Biochemistry, Christian Medical College, Bagayam, Vellore 632002, Tamil Nadu, India. Electronic address: premilaabraham@cmcvellore.ac.in.
authors.forename: Premila
authors.initials: P
authors.lastname: Abraham
authors.affiliation: Department of Anatomy, Christian Medical College, Bagayam, Vellore 632002, Tamil Nadu, India.
authors.forename: Bina
authors.initials: B
authors.lastname: Isaac
authors.affiliation: Department of Biochemistry, Christian Medical College, Bagayam, Vellore 632002, Tamil Nadu, India.
authors.forename: Dhayakani
authors.initials: D
authors.lastname: Selvakumar
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D007124:Immunoenzyme Techniques; D018836:Inflammation Mediators / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008550:Melatonin / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D000068698:Tenofovir / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D000975:Antioxidants; D018836:Inflammation Mediators; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D000068698:Tenofovir; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D008550:Melatonin
keywords: COX-2; NFκB signalling; Renal damage; TNFα; Tenofovir; iNOS