The mitochondrial dysfunction regulated by JAK2/STAT3 pathway leads to the necroptosis in the renal cells under patulin exposure

Abstract

Patulin (PAT) is a common mycotoxin widely found in various agricultural products and fruits, which has obvious toxic effects on animals and humans. Some studies have shown that PAT can cause nephrotoxicity, but the exact mechanism remains to be elucidated. In the present study, we investigated PAT-induced nephrotoxicity and the possible molecular mechanisms involved in its action. In vivo, the results showed that PAT affected the integrity of the glomerular basement membrane and peduncles, leading to necroptosis. We further demonstrated that PAT up-regulated the expression of JAK2, STAT3, RIPK1, RIPK3, and MLKL. This observation was also confirmed in MPC-5 cells. In vitro, pretreatment with Nec-1 (a specific inhibitor of necroptosis) or si-STAT3 resulted in a significant reduction in necroptosis and improved mitochondrial dysfunction. Notably, the pharmacological protection of mitochondrial function by SS-31 significantly attenuated the onset of PAT-induced necroptosis. Taken together, our study suggested that STAT3 activation, and mitochondrial dysfunction played critical roles in PAT-induced necroptosis in the kidney. These findings revealed the mechanisms by which PAT triggered necroptosis, potentially providing a new therapeutic strategy for PAT poisoning.