Abstract
Background
Clinical hypertension is associated with renal inflammation and elevated circulating levels of proinflammatory cytokines. IL-1 receptor antagonist (IL-1Ra) is one of the most important anti-inflammatory cytokines and plays a crucial role in inflammation. Inhibition of IL-1 may contribute to modulation of the Angiotensin II (AngII)-induced hypertension response. This study aimed to elucidate the effects of IL-1Ra and anti-IL-1beta antibody (01BSUR) on AngII-induced hypertension and renal inflammation.
Methods and results
To determine the contribution of IL-1Ra to AngII-induced renal inflammation, male wild-type (WT) and IL-1Ra-deficient (IL-1Ra−/−) mice were infused with AngII (1000ng/kg/min) using subcutaneous osmotic pumps for 14 days. We checked blood pressure, histological change, and several mRNA expressions 14 days after infusion. Fourteen days after infusion, systolic blood pressure (197±5 vs 169±9 mmHg, p<0.05) in IL-1Ra−/− mice significantly increased compared with WT mice. Furthermore, on day 14 of AngII infusion, plasma IL-6 was 5.9-fold higher in IL-1Ra−/− versus WT mice (p<0.001); renal preproendothelin-1 mRNA expression was also significantly higher in IL-1Ra−/− mice (p<0.05). To examine renal function, we analyzed 24-hour urinary protein excretion and serum levels of blood urea nitrogen, creatinine, and uric acid in IL-1Ra−/− and WT mice. On day 14 of Ang II infusion, all levels increased significantly in IL-1Ra−/− mice compared with WT mice, suggesting that IL-1Ra deficiency reduced renal function following Ang II infusion. In addition, renal histology revealed that glomerular injury (Figure upper panels: PAS staining) and tubulointerstitial fibrosis (Figure lower panels: Elastica Masson staining) increased significantly in Ang II-infused IL-1Ra−/− versus Ang II-infused WT mice. Finally, we administrated 01BSUR to both IL-1Ra−/− and WT mice, and 01BSUR treatment decreased AngII-induced hypertension (162±17 vs 204±6 mmHg, p<0.05) and renal damage (glomerular injury and fibrosis of the tubulointerstitial area) in both IL-1Ra−/− and WT mice compared with IgG2a treatment. These findings suggest that 01BSUR suppresses Ang II-induced inflammation and renal injury.
Conclusions
Inhibition of interleukin-1 by both endogenous IL-1Ra and exogenous 01BSUR decreased AngII-induced hypertension and renal damage in mice, suggesting suppression of IL-1 may provide an additional strategy to protect against renal damage in hypertensive patients.
Funding Acknowledgement
Type of funding source: Public grant(s) – National budget only. Main funding source(s): JSPS KAKENHI
Renal Denervation Prevents Immune Cell Activation and Renal Inflammation in Angiotensin II–Induced Hypertension
