Treatment with β-blocker nebivolol ameliorates oxidative stress and endothelial dysfunction in tenofovir-induced nephrotoxicity in rats

Abstract

BackgroundTenofovir disoproxil fumarate (TDF), a widely prescribed component in antiretroviral regimens, has been associated with nephrotoxicity. Nebivolol is a third generation selective β-1 adrenergic receptor blocker and may protect renal structure and function through the suppression of oxidative stress and enhancement of nitric oxide (NO) synthesis. We aimed to investigate whether nebivolol could be an effective therapeutic strategy to mitigate tenofovir-induced nephrotoxicity.MethodsWe allocated Wistar rats to four groups: control (C), received a standard diet for 30 days; NBV, received a standard diet for 30 days added with nebivolol (100 mg/kg food) in the last 15 days; TDF, received a standard diet added with tenofovir (300 mg/kg food) for 30 days; and TDF+NBV, received a standard diet added with tenofovir for 30 days and nebivolol in the last 15 days.ResultsLong-term exposure to tenofovir led to impaired renal function, induced hypertension, endothelial dysfunction and oxidative stress. Nebivolol treatment partially recovered glomerular filtration rate, improved renal injury, normalized blood pressure and attenuated renal vasoconstriction. Administration of nebivolol contributed to reductions in asymmetric dimethylarginine (ADMA) levels as well as increases in endothelial nitric oxide sintase (eNOS) accompanied by renin-angiotensin-aldosterone system downregulation and decreases in macrophage and T-cells infiltrate. Furthermore, nebivolol was responsible for the maintenance of the adequate balance of thiobarbituric acid reactive substances (TBARS) and glutathione (GSH) levels and it was associated with reductions in NADPH oxidase (NOX) subunits.ConclusionNebivolol holds multifaceted actions that promote an advantageous option to slow the progression of kidney injury in tenofovir-induced nephrotoxicity.

Administration of a single dose of lithium ameliorates rhabdomyolysis-associated acute kidney injury in rats

“…Glycerol-induced AKI model is characterized by enhanced renal oxidative stress [ 22 ] and protective elements, such as MnSOD, may be straightly associated with mechanisms underlying the mitigation of AKI [ 23 ]. Gly group exhibited a higher MnSOD renal protein abundance compared to Sham and Li groups.…”

“…al reported that precipitation of heme protein can generate toxic free radicals and induce oxidative damage to the renal tubule [ 45 ]. MnSOD is the major antioxidant scavenger present in the mitochondria and may be straightly associated with mechanisms underlying the protection against AKI [ 11 , 23 ]. Our Gly rats presented a higher MnSOD renal expression and a single dose of lithium attenuated this enzyme expression in the Gly+Li rats.…”

“…In addition, Gois et al showed a significant increase in plasma TBARS levels, as well as a higher MnSOD renal protein expression 3 and 24 hours after glycerol administration in a rhabdomyolysis-induced AKI model, respectively [ 14 ]. Moreover, despite the presence of oxidative stress, MnSOD renal protein expression might be upregulated due to the enhanced TBARS levels, indicating that redox state imbalance activated the mitochondrial enzymatic system in the damaged kidney [ 23 ]. Inhibition of GSK3 by lithium does not trigger antioxidant systems upon normal condition, but exacerbates its response under oxidative stress.…”

“…Inhibition of GSK3 by lithium does not trigger antioxidant systems upon normal condition, but exacerbates its response under oxidative stress. Notwithstanding MnSOD is an antioxidant heat shock protein responsive to renal damage, Gly+Li rats showed a decrease in the renal expression of this element probably due to the antioxidant action of lithium and the recovery of kidney injury [ 23 , 54 ].…”