Cisplatin is extensively used to treat malignancies. However, its clinical use is always limited due to the serious side effects, especially the nephrotoxicity. Matrine (MAT), a tetracyclic quinolizine alkaloid found in sophora genus, exerts multiple pharmacological roles, including anti‐oxidative stress, anti‐inflammation and anti‐apoptosis, but the role of MAT on acute kidney injury (AKI) has not been evaluated. Here, we found that MAT potently inhibited cell injury induced by cisplatin in HK2 cells in vitro, which was associated with the inhibition of oxidative injury and NF‐κB‐mediated inflammation. Moreover, MAT treatment could activate the SIRT3/OPA1 axis and subsequently suppress the mitochondrial fragmentation and improve mitochondrial function. More importantly, SIRT3 knockdown suppressed the deacetylation of OPA1, which blocked the protective role of MAT on cisplatin‐induced cell injury. In vivo, MAT treatment alleviated renal dysfunction, histological damage and inflammation induced by cisplatin in mice. Furthermore, consistent with the founding in vitro, MAT also activated SIRT3‐mediated deacetylation of OPA1 and alleviated mitochondrial dysfunction in AKI mice. Our study proved that MAT protected against cisplatin‐induced AKI by synergic anti‐oxidative stress and anti‐inflammation actions via SIRT3/OPA1‐mediated improvement of mitochondrial function, suggesting that MAT may be a novel and effective strategy for AKI.

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Macrophages (Mφ) infiltration is a common characteristic of acute kidney injury (AKI). Exosomes‐mediated cell communication between tubular epithelial cells (TECs) and Mφ has been suggested to be involved in AKI. Exosomes‐derived from injured TECs could regulate Mφ polarization during AKI. However, little is known regarding how activated Mφ regulates kidney injury. To explore the role of activated Mφ in the AKI process, we revealed that Mφ‐derived exosomes from AKI mice (ExosAKI) caused mitochondria damage and induced TECs injury. Then, we detected the global miRNA expression profiles of MφNC and MφAKI and found that among the upregulated miRNAs, miR‐195a‐5p, which regulates mitochondria metabolism in cancer, was significantly increased in MφAKI. Due to the enrichment of miR‐195a‐5p in ExosAKI, the miR‐195a‐5p level in the kidney was elevated in AKI mice. More interestingly, based on the high expression of pri‐miR‐195a‐5p in kidney‐infiltrated Mφ, and the reduction of miR‐195a‐5p in kidney after depletion of Mφ in AKI mice, we confirmed that miR‐195a‐5p may be produced in infiltrated Mφ, and shuttled into TECs via ExosMφ. Furthermore, in vitro inhibition of miR‐195a‐5p alleviated the effect of ExosAKI induced mitochondrial dysfunction and cell injury. Consistently, antagonizing miR‐195a‐5p with a miR‐195a‐5p antagomir attenuated cisplatin‐induced kidney injury and mitochondrial dysfunction in mice. These findings revealed that the Mφ exosomal miR‐195a‐5p derived from AKI mice played a critical pathologic role in AKI progression, representing a new therapeutic target for AKI.

Autophagy is a highly conserved cellular progress for the degradation of cytoplasmic contents including micromolecules, misfolded proteins, and damaged organelles that has recently captured attention in kidney diseases. Basal autophagy plays a pivotal role in maintaining cell survival and kidney homeostasis. Accordingly, dysregulation of autophagy has implicated in the pathologies of kidney diseases. In this review, we summarize the multifaceted role of autophagy in kidney aging, maladaptive repair, tubulointerstitial fibrosis and discuss autophagy-related drugs in kidney diseases. However, uncertainty still remains as to the precise mechanisms of autophagy in kidney diseases. Further research is needed to clarify the accurate molecular mechanism of autophagy in kidney diseases, which will facilitate the discovery of a promising strategy for the prevention and treatment of kidney diseases.