IL-18 deficiency ameliorates the progression from AKI to CKD.
Junjun LuanJingqi FuCongcong JiaoXiangnan HaoZixuan FengLingzi ZhuYixiao ZhangGuangyu ZhouHongyu LiWei YangPeter S T YuenJeffrey B KoppJingbo PiHua ZhouPublished in: Cell death & disease (2022)
Inflammation is an important factor in the progression from acute kidney injury (AKI) to chronic kidney disease (CKD). The role of interleukin (IL)-18 in this progression has not been examined. We aimed to clarify whether and how IL-18 limits this progression. In a folic acid induced renal injury mouse model, we studied the time course of kidney injury and renal IL-18 expression. In wild-type mice following injection, renal IL-18 expression increased. In parallel, we characterized other processes, including at day 2, renal tubular necroptosis assessed by receptor-interacting serine/threonine-protein kinase1 (RIPK1) and RIPK3; at day 14, transdifferentiation (assessed by transforming growth factor β1, vimentin and E-cadherin); and at day 30, fibrosis (assessed by collagen 1). In IL-18 knockout mice given folate, compared to wild-type mice, tubular damage and necroptosis, transdifferentiation, and renal fibrosis were attenuated. Importantly, IL-18 deletion decreased numbers of renal M1 macrophages and M1 macrophage cytokine levels at day 14, and reduced M2 macrophages numbers and macrophage cytokine expression at day 30. In HK-2 cells, IL-18 knockdown attenuated necroptosis, transdifferentiating and fibrosis.In patients with tubulointerstitial nephritis, IL-18 protein expression was increased on renal biopsies using immunohistochemistry. We conclude that genetic IL-18 deficiency ameliorates renal tubular damage, necroptosis, cell transdifferentiation, and fibrosis. The renoprotective role of IL-18 deletion in the progression from AKI to fibrosis may be mediated by reducing a switch in predominance from M1 to profibrotic M2 macrophages during the process of kidney repair.
Keyphrases
- acute kidney injury
- chronic kidney disease
- wild type
- mouse model
- transforming growth factor
- oxidative stress
- poor prognosis
- protein kinase
- type diabetes
- high glucose
- cardiac surgery
- binding protein
- end stage renal disease
- induced apoptosis
- gene expression
- single cell
- skeletal muscle
- signaling pathway
- epithelial mesenchymal transition
- ultrasound guided
- drug induced
- diabetic rats
- pi k akt
- peritoneal dialysis
- cell cycle arrest