PCSK9 causes inflammation and cGAS/STING pathway activation in diabetic nephropathy

Abstract Our previous research revealed that an increase in PCSK9 is linked to aggravated inflammation in the kidneys of mice affected by a high‐fat diet and streptozotocin (HFD/STZ) or in HGPA‐induced HK‐2 cells. Furthermore, the cGAS/STING pathway has been reported to be involved in diabetic nephropathy (DN). Therefore, in this study, we aimed to examine the correlation between the proinflammatory effect of PCSK9 and the cGAS/STING pathway in DN. We used PCSK9 mAbs to inhibit PCSK9 in vivo and PCSK9 siRNA in vitro and measured the inflammatory phenotype in HFD/STZ‐treated mice or HGPA‐induced HK‐2 cells, and observed decreased blood urea nitrogen, creatinine, UACR, and kidney injury in response to the PCSK9 mAb in HFD/STZ‐treated mice. Moreover, IL‐1 β, MCP‐1, and TNF‐α levels were reduced by the PCSK9 mAb in vivo and PCSK9 siRNA in vitro. We observed increased mtDNA damage and activation of the cGAS‐STING signaling pathway during DN, as well as the downstream targets p‐TBK1, p‐NF‐κB p65, and IL‐1β. In a further experiment with an HGPA‐induced DN model in HK‐2 cells, we revealed that mtDNA damage was increased, which led to the activation of the cGAS/STING system and its downstream targets. Notably, the cGAS‐STING signaling pathway was inhibited by the PCSK9 mAb in vivo and PCSK9 siRNA in vitro. In addition, inhibition of STING with C‐176 in HGPA‐induced HK‐2 cells markedly blocked inflammation. In conclusion, we report for the first time that PCSK9 triggers mitochondrial DNA damage and activates the cGAS‐STING pathway in DN, which leads to a series of inflammation cascades. PCSK9‐targeted intervention can effectively reduce DN inflammation and delay its progression. Moreover, the inhibition of STING significantly abrogated the inflammation triggered by HGPA in HK‐2 cells.