| First Author | Zhang S | Year | 2023 |
| Journal | Redox Biol | Volume | 66 |
| Pages | 102860 | PubMed ID | 37633049 |
| Mgi Jnum | J:341116 | Mgi Id | MGI:7528064 |
| Doi | 10.1016/j.redox.2023.102860 | Citation | Zhang S, et al. (2023) LRRK2 aggravates kidney injury through promoting MFN2 degradation and abnormal mitochondrial integrity. Redox Biol 66:102860 |
| abstractText | Mitochondrial dysfunction is one of the key features of acute kidney injury (AKI) and associated fibrosis. Leucine-rich repeat kinase 2 (LRRK2) is highly expressed in kidneys and regulates mitochondrial homeostasis. How it functions in AKI is unclear. Herein we reported that LRRK2 was dramatically downregulated in AKI kidneys. Lrrk2(-/-) mice exhibited less severity of AKI when compared to wild-type counterparts with less mitochondrial fragmentation and decreased reactive oxygen species (ROS) production in proximal renal tubular cells (PTCs) due to mitofusin 2 (MFN2) accumulation. Overexpression of LRRK2 in human PTC cell lines promoted LRRK2-MKK4/JNK-dependent phosphorylation of MFN2(Ser27) and subsequently ubiquitination-mediated MFN2 degradation, which in turn exaggerated mitochondrial damage upon ischemia/reperfusion (I/R) mimicry treatment. Lrrk2 deficiency also alleviated AKI-to-chronic kidney disease (CKD) transition with less fibrosis. In vivo pretreatment of LRRK2 inhibitors attenuated the severity of AKI as well as CKD, potentiating LRRK2 as a novel target to alleviate AKI and fibrosis. |
