What is the clinical evidence from this study?

Study design: Other. Population: Doxorubicin-induced nephrotoxicity. Intervention: Fenofibrate and pioglitazone vs. Doxorubicin alone. Primary outcome: Nephrotoxicity markers (serum creatinine, BUN, oxidative stress, inflammation, apoptosis).

April 27, 2022Open Access

Mechanistic Study on the Effect of Peroxisome Proliferator Activated Receptor Agonist Drugs against Doxorubicin Induced Nephrotoxicity in Rats

AAAzza A. AliPrince Sattam Bin Abdulaziz University ESEman B. SaadSinai University RHRana HassanDelta Air Lines (United States)

Key Result

Fenofibrate, pioglitazone, and their combination significantly attenuated doxorubicin-induced nephrotoxicity in rats through modulation of the p38-MAPK/NF-κB p65 pathway.

Structured PICO

Does fenofibrate and/or pioglitazone prevent doxorubicin-induced nephrotoxicity in rats?

Population

Male Sprague-Dawley rats weighing 200 to 230 g

Intervention

Fenofibrate (100 mg/kg p.o) and/or pioglitazone (10 mg/kg p.o) for 15 days, with doxorubicin (15 mg/kg i.p on 11th day)

Comparator

Control (50% corn oil + 50% DMSO p.o) and doxorubicin alone

Outcome

Nephroprotective effects measured by serum creatinine, BUN, oxidative stress markers (GSH, MDA), inflammatory markers (TNF-α, NF-κB p65, IL-1β), apoptotic markers (p38-MAPK, Casp-3), and histological assessmentsurrogate

Fenofibrate and pioglitazone, especially in combination, show promising protective effects against doxorubicin-induced nephrotoxicity in rats via modulation of the p38-MAPK/NF-κB p65 pathway.

Abstract

Abstract Doxorubicin (DOX) is one of the basic chemotherapeutic drugs for cancer treatment, but its use is restricted due to noxious side effects. One of the major side effects that restrict its medical use is kidney failure. The PPAR-α agonists have been displayed to have beneficial effects against drug-induced nephropathy in animals. Similarly, PPAR-γ agonists have revealed nephroprotection by haemodynamic, vascular, anti-inflammatory, anti-oxidant and metabolic effects. This study examined the nephroprotective effects of fenofibrate (FENO) and pioglitazone (PIO) against the nephrotoxicity induced by doxorubicin in rats and illustrate the probable mechanisms underlying these protective effects. For this purpose, Male Sprague-Dawley rats weighing (200 to 230 g) were allocated into seven groups treated for 15 days as following: control (50% corn oil + 50% DMSO p.o), fenofibrate (100 mg/kg p.o) and pioglitazone (10 mg/kg p.o) as well as four groups of DOX (15 mg/kg i.p on 11th day). DOX groups included DOX alone and DOX with protective drugs fenofibrate, pioglitazone or both of them. As a result of doxorubicin nephrotoxicity; serum creatinine and blood urea nitrogen (BUN) were significantly elevated. Moreover, renal glutathione (GSH) was significantly reduced while tissue lipid peroxidation malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), nuclear factor-kappa B p65 (NF-κB p65), interleukin-1β (IL-1β), p38 mitogen activated protein kinase (p38-MAPK) and caspase-3 (Casp-3) were significantly increased. Administration of fenofibrate and pioglitazone either alone or in combination significantly attenuated DOX-induced injury by suppression of oxidative stress, inflammation and apoptosis. The above-mentioned biochemical markers were affirmed by histological assessment. In conclusion, Fenofibrate, pioglitazone and their combination possess promising protective effects against doxorubicin-induced nephrotoxicity through modulation of p38-MAPK/ NF-κB p65 pathway with superiority to the combination.

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