IGF2BP3-stabilized CAMK1 regulates the mitochondrial dynamics of renal tubule to alleviate diabetic nephropathy

CAMK1 has been shown to be involved in human disease progression via regulating mitochondrial dynamics. However, whether CAMK1 mediates mitochondrial dynamics to regulate diabetic nephropathy (DN) process remains unclear. Mice were injected with streptozotocin (STZ) to mimic diabetic mice models in vivo, and mice with proximal tubule-specific knockout of CAMK1 (CAMK1-KO) were generated. HK-2 cells were treated with high-glucose (HG) to mimic DN cell model in vitro. Histopathological analysis was performed to confirm kidney injury in mice. ROS production and apoptosis were assessed by DHE staining and TUNEL staining. Mitochondria morphology was observed and analyzed by electron microscopy. Mitochondrial membrane potential was detected by JC-1 staining, and cell proliferation was measured by EdU assay. The mRNA and protein expression were examined by qRT-PCR, western blot and immunostaining. RNA interaction was confirmed by RIP assay and dual-luciferase reporter assay. The mRNA stability was tested by actinomycin D treatment, and m6A level was examined by MeRIP assay. CAMK1 was reduced in DN patients and STZ-induced diabetic mice. Conditional deletion of CAMK1 aggravated kidney injury and promoted mitochondrial fission in diabetic mice. CAMK1 overexpression inhibited mitochondrial fission to alleviate HG-induced HK-2 cell apoptosis. IGF2BP3 promoted the stability of CAMK1 mRNA by m6A modification. IGF2BP3 inhibited mitochondrial fission to repress cell apoptosis in vitro and kidney injury in vivo by increasing CAMK1 expression. IGF2BP3-mediated CAMK1 mRNA stability alleviated DN progression by inhibiting mitochondria fission. [Display omitted] •CAMK1 is lowly expressed in DN patients and STZ-induced diabetic mice.•CAMK1 deletion aggravates kidney injury by promoting mitochondrial fission.•CAMK1 overexpression inhibits mitochondrial fission to alleviate cell apoptosis.•IGF2BP3 enhances the stability of CAMK1 mRNA by m6A modification.•IGF2BP3 increases CAMK1 expression to repress mitochondrial fission.