Objective To investigate the changes of the pro-inflammatory mediator S100A8/9 and NLRP3/Caspase-1/IL-1β pathway in rat kidney aging model induced by D-galactose. Methods According to weight 12 SD rats were divided into control group and D-galactose group, through the back of the neck subcutaneous injection of D-galactose (150 mg/kg) establishing the model of rat kidney aging model. After 8 weeks, kidney samples were collected under anesthesia, SA-β-Gal staining was performed, and the mRNA expression levels of aging related genes p21, p16 and p53 were detected by qRT-PCR; histopathological changes of kidney were observed by HE and Masson staining; contents of urea nitrogen and creatinine in serum, and contents of CAT、GSH-PX、SOD、MDA from kidney tissues were detected; DHE staining was used to observe the changes of ROS level in kidney tissue; protein expression levels of Collagen III, α-SMA and TGF-β1 in tissues were detected by Western blot; immunofluorescence staining was used to detect the protein expression level of S100A8/9, and Western blot assay was used to detect the expression levels of key factors in NLRP3/Caspase-1/IL-1β inflammatory pathway. The renal senescence model of HK-2 cells was constructed using H2O2 in vitro, and the expression levels of senescence proteins p21、p16 and the mRNA expression levels of inflammatory factors IL-18、TNF-α were detected. The senescence of cells was observed by SA-β-Gal staining. Then paquinimod, an S100A8/9 inhibitor, was used to intervene in the aging model, and the expression levels of related proteins in the S100A8/9 and NLRP3/Caspase-1/IL-1β pathways were detected. Results Compared with the control group, the mRNA expression levels of aging genes p21, p16 and p53 in kidney tissue of rats in D-galactose group were significantly increased（P ＜ 0.01）, and SA-β-Gal staining showed a significant increase in senescent cells（P ＜ 0.01）. Contents of BUN and CREA in serum increased（P ＜ 0.05）. The activities of CAT, GSH-PX and SOD decreased significantly（P ＜ 0.01）, while the activities of MDA increased significantly（P ＜ 0.01）. The protein expressions of Collagen III, α-SMA and TGFβ1 were increased（P ＜ 0.05）. ROS content in tissues increased（P ＜ 0.05）. In D-galactose group, the glomeruli were atrophied and absent to a certain extent, the lumen of the renal sacs and the tubular lumen of the renal tubules were enlarged, the nuclei were deeply stained and constricted, and a large number of collagen fibers were deposited. S100A8 and S100A9 protein expression increased（P ＜ 0.01）. The protein expression of NLRP3, Caspase-1 and IL-1β in the NLRP3/Caspase-1/IL-1β inflammatory pathway was increased（P ＜ 0.05）. After H2O2 induced senescence of HK-2 cells, the use of S100A8/9 inhibitor paquinimod alleviated the senescence of HK-2 cells, and the expression levels of senescence proteins p21、p16 and the mRNA expressions of inflammatory factors IL-18、TNF-α were decreased（P ＜ 0.05，P ＜ 0.01）, and the number of senile cells was decreased by SA-β-Gal staining（P ＜ 0.01）.The treatment also inhibited the expressions of S100A8 and S100A9 proteins （P ＜ 0.01）and the expressions of NLRP3, Caspase-1 and IL-1β proteins （P ＜ 0.05 or P ＜ 0.01）. Conclusions S100A8/9 participate in chronic inflammatory response by activating the NLRP3/Caspase-1/IL-1β pathway, thereby promoting D-gal induced renal aging process.