Pirfenidone attenuates gentamicin-induced acute kidney injury by inhibiting inflammasome-dependent NLRP3 pathway in rats

Abstract

Acute kidney injury (AKI) is an abrupt and usually reversible decline in renal function. AKI is considered one of the main drawbacks of the use of gentamicin that critically limits its clinical use. In this study, pirfenidone, an oral antifibrotic drug, was given to rats (200 mg/kg, p.o., daily) for seven days alone before the initiation of gentamicin treatment and continued for seven days alongside daily gentamicin injections. In gentamicin group, gentamicin was given to Wistar rats (100 mg/kg, i.p., daily) for seven days to induce AKI. Pirfenidone managed to alleviate gentamicin-induced AKI by improving kidney function parameters including serum creatinine, blood urea nitrogen (BUN), proteinuria, relative kidney-to-body weight ratio and creatinine clearance. Pirfenidone decreased cytotoxicity induced by gentamicin by decreasing lactate dehydrogenase (LDH) activity and improving histologic picture of tubules and glomeruli. Pirfenidone also alleviated oxidative stress induced by gentamicin by reducing malondialdehyde (MDA) and elevating reduced glutathione (GSH). Pirfenidone prevented the upregulated inflammasome pathway markers in the kidney. It succeeded in decreasing toll like recpetor-4 (TLR4), nuclear factor-kappa B (NF-κB), nucleotide-binding oligomerization domain [NOD]-like pyrin domain containing protein 3 (NLRP3), caspase-1, interleukin-1β (IL-1β) and IL-18 levels. Additionally, Pirfenidone caused a decrease in macrophage infiltration displayed by reduction in renal monocyte chemoattractant protein-1 (MCP-1) levels. To sum up, pirfenidone can effectively mitigate gentamicin-induced AKI by inhibiting oxidative stress, macrophage infiltration and inflammasome-dependent NLRP3 pathway-induced inflammation.