Tetramethylpyrazine attenuates sodium arsenite-induced acute kidney injury by improving the autophagic flux blockade via a YAP1-Nrf2-p62-dependent mechanism.

Abstract

With increased application, sodium arsenite (AS III)-induced acute kidney injury (AI-AKI) is becoming a new clinical challenge, but its potential pathogenesis remains poorly studied. Our previous data demonstrated that inducing autophagy and mitochondrial dysfunction in renal tubular cells are important links of AI-AKI and could be inhibited by tetramethylpyrazine (TMP). Recently, co-transcription factor YAP1 is reported to control autophagy and is mandatory to stimulate autophagic flux. This study constructed in vitro and in vivo models using clinically related dosages of AS III. Mitophagy, upregulated YAP1 expression, and Nrf2 activation were observed, with upregulation of p62 representing the occurrence of autophagic flux blockade. In HK-2 cells, oxidative stress induced by AS III promoted sustained Nrf2 activation, which enhanced p62 transcription at an early phase. Subsequently, p62 accumulation induced Nrf2 nuclear translocation, which in turn promoted p62 expression, forming a feedback loop to induce autophagic flux blockade, which was aggravated by the autophagic flux blocker chloroquine (CQ). TMP reversed such processes and protected tubular cells, while silencing YAP1 and Nrf2 attenuated TMP renoprotections. YAP1 agonist PY-60 increased Nrf2 expression, while YAP1 knockdown counteracted it and diminished TMP effect on autophagic flux. Furthermore, blocking Nrf2 caused YAP1 accumulation. CO-IP and immunofluorescence co-localization results confirmed co-nuclear translocations of YAP1 bound to dissociated Nrf2 that induced autophagic flux blockade. In conclusion, the present study identified novel mechanisms that TMP alleviated AI-AKI by improving the autophagic flux blockade via a YAP1-Nrf2-p62-dependent mechanism.