# Renoprotective impact of tiron against diclofenac-induced nephrotoxicity: targeting TLR4/NF-κB/NLRP3/Caspase-1/IL1-β pathway

## TL;DR

This study shows that tiron protects mice kidneys from damage caused by diclofenac by reducing inflammation and oxidative stress.

## Contribution

The study identifies tiron as a potential renoprotective agent against diclofenac-induced nephrotoxicity via modulation of specific inflammatory pathways.

## Key findings

- Tiron reduced serum creatinine and blood urea nitrogen levels in mice with diclofenac-induced nephrotoxicity.
- Tiron improved kidney structure and reduced oxidative stress markers like MDA while increasing GSH and SOD.
- Tiron downregulated the TLR4/NF-κB/NLRP3/Caspase-1/IL1-β inflammatory pathway in the kidneys.

## Abstract

Nephrotoxicity is a documented side effect of non-steroidal anti-inflammatory drugs (NSAIDs) like diclofenac (Diclo). Thus, this study was executed to assess the renoprotective effect of tiron against Diclo-induced nephrotoxicity. Nephrotoxicity was induced in mice by single administration of Diclo (300 mg/kg, po). Mice received tiron (140 and 280 mg/kg, ip) for 7 successive days, Diclo was administered on day 7 after 1 h of tiron injection. Diclo significantly deteriorated kidney function and structure; Diclo injection produced a marked increase in serum levels of creatinine, urea and blood urea nitrogen (BUN) as well as profound escalation in levels of creatinine, total protein and albumin in urine. Moreover, Diclo induced oxidative stress manifested by substantial increase in malondialdehyde (MDA) and notable decrease in reduced glutathione (GSH) level and superoxide dismutase (SOD) activity. Additionally, Diclo significantly increased renal levels of toll-like receptor 4 (TLR-4), nuclear factor kappa B (NF-κB), NOD-like receptor protein 3 (NLRP3), apoptosis associated speck-like protein, Caspase-1 and interleukin (IL)-1β, besides elevation in renal expression of cyclooxygenase (COX)-II. The results of these biomarkers were further confirmed by histopathological analysis. Injection of tiron in both doses markedly improved Diclo-induced alterations. Hence, tiron could be a promising candidate in alleviating nephrotoxicity induced by NSAIDs following further clinical research.

Tiron exerted renoprotective effect against diclofenac-induced nephrotoxicity in mice via decreasing levels of serum creatinine and blood urea nitrogen.Tiron improved kidney architecture as evidenced by histopathological observations.Tiron possessed anti-oxidant effects through decreasing MDA content and increasing GSH level and SOD activity.Tiron decreased inflammation via down-regulating TLR4/NF-κB/NLRP3/Caspase-1/IL1-β pathway.

Tiron exerted renoprotective effect against diclofenac-induced nephrotoxicity in mice via decreasing levels of serum creatinine and blood urea nitrogen.

Tiron improved kidney architecture as evidenced by histopathological observations.

Tiron possessed anti-oxidant effects through decreasing MDA content and increasing GSH level and SOD activity.

Tiron decreased inflammation via down-regulating TLR4/NF-κB/NLRP3/Caspase-1/IL1-β pathway.