Madecassoside Ameliorates Cisplatin-Induced Nephrotoxicity by Inhibiting Activation of the Mitogen Activated Protein Kinase Pathway.

Nephrotoxicity is a major side effect of cisplatin. Apoptosis, oxidative stress, inflammation, and the MAPK signaling pathway activation are concerned with the pathophysiology of cisplatin-induced acute kidney injury (AKI). Madecassoside (MA), an active constituent of Centella asiatica, has anti-oxidative and anti-inflammatory effects. The present research aim to investigate the underlying protective mechanisms of MA on cisplatin nephrotoxicity. Pretreatment of mice with MA markedly ameliorated cisplatin-induced renal tubular cell injury evidenced by the improvement of kidney function and kidney morphology and blocked upregulation of kidney injury biomarkers (kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL)). Cisplatin-induced renal cell apoptosis, inflammation, and oxidative stress were also prevented by MA treatment. Consistent with the in vivo results, MA pretreatment attenuated cisplatin-induced renal cell apoptosis, oxidative stress, and inflammation. Transcriptome analysis using RNA-sequencing suggested that the MAPK signaling pathway was the most affected, and MA could inhibit cisplatin-induced MAPK signaling pathway activation in vivo and in vitro. In summary, MA treatment ameliorated cisplatin-induced renal tubular damage possibly by decreasing activation of the MAPK signaling pathway, suggesting its potential for the treatment of AKI.