Hypertensive renal injury (HRI) is a main cause of end-stage renal diseases, and CD4+ T cells and the secreted inflammatory cytokines contribute to the progress of HRI. However, the exact mechanisms remain unidentified in HRI, and there is still a shortage of effective treatments. Here, we aim to explore the role of interleukin-22 (IL-22) and its underlying mechanism in HRI. Serum IL-22 level and peripheral Th22 cells frequency in patients with HRI were detected by ELISA and flow cytometry respectively. Angiotension II (Ang II) was infused subcutaneously to C57BL/6 mice for 28 days. Hypertensive mice were treated with recombinant IL-22 (rIL-22), anti-IL-22 antibody, or JAK2/STAT3 pathway blocker AG-490 respectively. Blood pressure (BP), urinary albumin/creatinine ratio (UACR), serum creatinine (Scr) and renal histopathology were measured; renal Th22 cells proportion were evaluated; inflammatory factors were evaluated by ELISA; JAK2/STAT3 pathway and fibrosis related factors expression in kidney were detected by Western blot. Serum IL-22 and Th22 cells proportion in kidney of mice were elevated after Ang II infusion. Compared to Ang II-infused mice, treatment with rIL-22 resulted in further increased UACR, Scr, renal pathological damage, inflammation and renal fibrosis, accompanied by elevated BP and JAK2/STAT3 pathway activation. Conversely, anti-IL-22 antibody reduced inflammation, renal fibrosis and BP in Ang II treated mice. AG490 could compromised the above effects of rIL-22. Taken together, recombinant IL-22 may aggravate hypertensive renal damage mediated by Ang II in mice, which may be through promoting JAK2/STAT3 pathway activation. Anti-IL-22 antibody exerts the opposite effects. These data suggest the IL-22 signaling maybe a novel therapeutic target for the treatment of hypertensive renal injury.Copyright © 2022. Published by Elsevier B.V.