Pathogenesis of Anti HIV Drug Tenofovir Induced Renal Damage Possible Roles of Oxidative stress Nitrosative stress and NFκB Pathway

Abstract

Tenofovir disoproxil fumarate is a commonly used drug for the treatment of AIDS. However, the usage of the drug is often limited by its nephrotoxicity after long time usage (2-9 years). Tenofovir and related nucleotide analogs have primarily been associated with proximal tubular dysfunction and acute kidney injury. Tenofovir targets the proximal tubular mitochondria. However, the mechanism of TDF induced mitochondrial damage and consequence of mitochondrial damage is not known. OBJECTIVES: 1. Standardize a rat model of Tenofovir induced renal damage 2. Assess the effect of tenofovir on mitochondrial structure and function in the kidney. 3. Investigate the role of oxidative stress and nitrosative stress in the tenofovir induced renal damage using rat as a model. 4. Investigate the role of NFand#954;B activation and its target genes, PARP activation in the tenofovir induced renal damage. 5. Study the effect of melatonin, a potent anti-oxidant, anti-inflammatory agent and NFand#954;B inhibitor on tenofovir - induced renal damage. Nephrotoxicity is one of the most common side effects of chronic tenofovir therapy in HIV infected patients and may necessitate discontinuation of chemotherapy. Agents that can reduce the incidence or severity of tenofovir related nephrotoxicity are urgently needed. Melatonin has been shown to reduce the toxicity of many drugs and in some cases improve their efficacy. The results of our study provide evidence for melatonin as an agent that can protect against TDF nephrotoxicity. Melatonin is safe, nontoxic, inexpensive, and available in pure form for human use as a drug. Execution of clinical trials using melatonin as a renoprotective agent in HIV infected patients on tenofovir therapy is our primary goal. Conducting preclinical studies to evaluate the effectiveness of resveratrol /hesperidin in the attenuation of tenofovir nephrotoxicity. Investigating whether the administration of MitoQ protects against TDF induced proximal tubular mitochondrial injury and dysfunction, and nephropathy in rats.