Baicalein acts as a nephroprotectant that ameliorates colistin-induced nephrotoxicity by activating the antioxidant defence mechanism of the kidneys and down-regulating the inflammatory response

Abstract

Background: Nephrotoxicity is the major adverse effect patients experience during colistin therapy. The development of effective nephroprotective agents that can be co-administered during polymyxin therapy remains a priority area in antimicrobial chemotherapy.

Objectives: To investigate the nephroprotective effect of baicalein, a component of the root of Scutellaria baicalensis, against colistin-induced nephrotoxicity using a mouse model.

Methods: C57BL/6 mice were randomly divided into the following groups: control, baicalein 100 mg/kg/day (administered orally), colistin (18 mg/kg/day administered intraperitoneally) and colistin (18 mg/kg/day) plus baicalein (25, 50 and 100 mg/kg/day). After 7 day treatments, histopathological damage, the markers of renal functions, oxidative stress and inflammation were examined. The expressions of Nrf2, HO-1 and NF-κB mRNAs were also further examined using quantitative RT-PCR examination.

Results: Baicalein co-administration markedly attenuated colistin-induced oxidative and nitrative stress, apoptosis, the infiltration of inflammatory cells, and caused decreases in IL-1β and TNF-α levels (all P < 0.05 or 0.01) in the kidney tissues. Baicalein co-administration up-regulated expression of Nrf2 and HO-1 mRNAs and down-regulated the expression of NF-κB mRNA, compared with those in the colistin alone group.

Conclusions: To the best of our knowledge, this is the first study demonstrating the protective effect of baicalein on colistin-induced nephrotoxicity and apoptosis by activating the antioxidant defence mechanism in kidneys and down-regulating the inflammatory response. Our study highlights that oral baicalein could potentially ameliorate nephrotoxicity in patients undergoing polymyxin therapy.

Figure 1.

Baicalein attenuates colistin-induced nephrotoxicity in mice. (a) Pathways of polymyxin-induced nephrotoxicity in mouse kidney tissues and the putative nephroprotective mechanism of baicalein. (b) and (c) Levels of serum BUN and CRE, respectively, in mice treated with colistin and/or baicalein. Results are presented as the mean ± SD (n = 10 in each group). **P < 0.01 compared with the untreated control. ^#P < 0.05 and ^##P < 0.01 compared with the colistin treatment group. Bai, baicalein.

Figure 2.

Representative histopathological changes in kidneys of mice treated with colistin and/or baicalein. (a) Control group: no damage. (b) Baicalein group: no damage. (c) Colistin (18 mg/kg/day) group: extensive damage. (d) Colistin (accumulated dose 126 mg/kg) plus baicalein (accumulated dose 175 mg/kg): intermediate damage. (e) Colistin plus baicalein (accumulated dose 350 mg/kg): mild damage. (f) Colistin plus baicalein (accumulated dose 700 mg/kg): minor damage. (g) SQS values are presented as the mean ± SD (n = 4). **P < 0.01 compared with the untreated control. ^#P < 0.05 and ^##P < 0.01 compared with the colistin treatment group. Filled arrows indicate marked tubular degeneration, necrosis and tubular dilation, arrowheads indicate cast formation and the open arrow indicates infiltration of inflammatory cells. Haematoxylin–eosin staining. Magnification: ×20. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 3.

Baicalein attenuates colistin-induced activation of caspase-9 (a), caspase-3 (b) and the inflammatory mediators IL-1β (c) and TNF-α (d) in the kidney tissue of mice treated with colistin. ELISA results are presented as the mean ± SD (n = 10 in each group). **P < 0.01 compared with the untreated control. ^#P < 0.05 and ^##P < 0.01 compared with the colistin treatment group.