Interleukin-22 attenuates renal tubular cells inflammation and fibrosis induced by TGF-ß1 through Notch1 signaling pathway.

Transforming growth factor-ß1 (TGF-ß1) is a crucial factor implicated in the development of renal inflammation and tubulointerstitial fibrosis (TIF). The cytokine interleukin 22 (IL-22) was previously reported to involve in the pathogenesis of chronic inflammatory diseases, however recent studies showed that IL-22 could reduced inflammatory responses and tissue damage. In the present study, we aim to investigate the role and mechanisms of IL-22 in renal tubular cells inflammation and fibrosis induced by TGF-ß1. HK-2 cells were treated with TGF-ß1 in the presence of IL-22 or the Notch pathway inhibitor dibenzazepine (DBZ) for 48 h. Collagen I (Col I), fibronectin (FN), α-smooth muscle actin (α-SMA), vimentin and E-Cadherin were detected by western blot, proinflammatory factors (TNF-α, IL-6) and chemokines (MCP-1, RANTES) were evaluated by ELISA. Jagged1, Notch1, NICD1, and Hes1 were also detected by western blot. We found TGF-ß1 increased the levels of Col I, FN, α-SMA and vimentin in HK-2 cells compared with control, and decreased E-Cadherin level, however, IL-22 restored their expressions partly. IL-22 reduced overexpression of proinflammatory factors (TNF-α, IL-6) and chemokines (MCP-1, RANTES) levels induced by TGF-ß1, along with down-regulation of Jagged1, Notch, NICD1 and Hes1. Fibrosis and inflammation in renal tubular cells induced by TGF-ß1 could be attenuated by IL-22, and the effects were similar to DBZ treatment. Collectively, our study shows that IL-22 exerts a protective role in renal fibrotic and inflammatory responses induced by TGF-ß1 in vitro, which may be through inhibiting Jagged1/Notch1 signaling pathway activation.

Irbesartan may relieve renal injury by suppressing Th22 cells chemotaxis and infiltration in Ang II-induced hypertension.

Angiotensin II (Ang II) as an important pathogenic factor, has been implicated in the pathogenesis of hypertension and associated renal injury, and inhibition of Ang II can reduce renal inflammation and exert renal protective effects. In the present study, we determine the infiltration of Th22 cells in kidney and serum IL-22 level in hypertensive renal injury, and explore the effects and mechanisms of a widely used angiotensin II type 1 receptor blocker irbesartan on Th22 cells infiltration and related renal injury. Hypertension was induced by administering 1.5 mg/kg Ang II subcutaneously daily in C57BL/6 mice for 28 days. The mice were additionally treated by irbesartan or amlodipine. Renal Th22 lymphocytes frequency was evaluated through flow cytometry, serum IL-22 was detected by ELISA, and renal histopathological changes were also detected. The levels of renal chemokines (CCL20, CCL22, CCL27) and serum proinflammatory factors (IL-1ß, IL-6, TNF-α) were measured by ELISA. Renal expression of alpha-smooth muscle actin (α-SMA), Fibronectin (FN) and collagen I (Col I) were evaluated by western blot. Chemotaxis assay and co-culture assay were conducted to clarify the effect of irbesartan on Th22 cells chemotaxis and differentiation in vitro. Our results showed in Ang II-infused hypertension mice, irbesartan suppressed renal Th22 cells accumulation as well as CCL20, CCL22, CCL27 expression. Serum IL-22, IL-1ß, IL-6 and TNF-α concentrations wasere also reduced, in addition to inhibited renal expression of α-SMA, FN and Col I. Irbesartan treatment lowered blood pressure, urinary protein and renal pathological damage. In vitro, irbesartan could abrogate the Th22 cells chemotaxis and differentiation, compared to control and amlodipine groups. Our study reveals a new pharmacological mechanism that irbesartan ameliorates inflammation and fibrosis in hypertensive renal injury induced by Ang II, maybe through inhibiting Th22 cells chemotaxis and infiltration, which provides a new theoretical basis and therapeutic target for hypertensive renal injury.