非对称性二甲基精氨酸通过激活铁死亡促进 小鼠早期肾损伤.

AIM: To investigate whether asymmetric dimethylarginine （ADMA）, an endogenous nitric oxide synthase （NOS） inhibitor, induces early kidney injury in mice through ferroptosis. METHODS: Sixteen 8-week-old SPF C57BL/6 male mice were randomly assigned to control group （n=8） and experimental group （n=8）. The experimental mice were orally administered with ADMA （60 mg·kg-1·d-1） daily for 16 weeks, while the control mice were orally administered with an equal volume of saline daily. After the treatment, glucose tolerance and insulin tolerance were measured in both groups. Serum samples were collected to measure ADMA levels, total cholesterol （TC）, triglycerides （TG）, and high-density lipoprotein cholesterol （HDL-C） levels. Blood urea nitrogen （BUN） levels were also determined. Kidney tissue samples were collected to assess pathological morphology, interleukin-6 （IL-6） and IL-1β levels, iron content, nitric oxide （NO） levels, malondialdehyde （MDA） levels, superoxide dismutase （SOD） activity, and the protein expression of endothelial NOS （eNOS）, inducible NOS （iNOS）, glutathione peroxidase 4 （GPX4）, Bcl2, Bax and caspase-1. RESULTS: Compared with the control group, the ADMA-treated mice showed impaired glucose tolerance and insulin sensitivity, indicating abnormal glucose metabolism. Serum TG and TC levels were elevated （P<0. 01）, while HDL-C level was decreased （P<0. 05）, indicating abnormal lipid metabolism. Additionally, ADMA directly induced early renal injury in mice resembling chronic kidney failure, characterized by glomerular hypertrophy, glomerular mesangial cell hypertrophy and increased BUN levels （P<0. 01）, as well as significantly elevated levels of pro-inflammatory cytokines IL-6 and IL-1β （P<0. 01）. Moreover, the ADMA-treated mice exhibited increased ADMA levels in kidney tissue （P<0. 01）, reduced expression of eNOS protein and total NO levels, but significantly increased expression of iNOS protein （P<0. 01）. Furthermore, kidney tissue analysis revealed iron overload, increased MDA levels, decreased SOD activity, decreased expression of GPX4 protein and anti-apoptotic protein Bcl2 （P<0. 01）, and increased expression of apoptosis markers Bax and caspase-1 proteins （P<0. 05 or P<0. 01）. CONCLUSION: ADMA may induce early kidney injury in mice through ferropotosis. [ABSTRACT FROM AUTHOR]