Nobiletin resolves left ventricular and renal changes in 2K-1C hypertensive rats
Metee Iampanichakul, Anuson Poasakate, Prapassorn Potue, Siwayu Rattanakanokchai, Putcharawipa Maneesai, Parichat Prachaney, Wannapa Settheetham‐Ishida, Poungrat Pakdeechote
Abstract
Abstract This study investigated the effects of nobiletin on cardiorenal changes and the underlying mechanisms involved in two-kidney, one-clip (2K-1C) hypertension. 2K-1C rats were treated with nobiletin (15 or 30 mg/kg/day) or losartan (10 mg/kg/day) for 4 weeks ( n = 8/group). Nobiletin (30 mg/kg) reduced high levels of blood pressure and circulating angiotensin II and angiotensin-converting enzyme activity in 2K-1C rats. Left ventricular (LV) dysfunction and remodelling in 2K-1C rats were alleviated in the nobiletin-treated group ( P < 0.05). Nobiletin reduced the upregulation of Ang II type I receptor (AT 1 R)/JAK (Janus kinase)/STAT (signal transducer and activator of transcription) protein expression in cardiac tissue of 2K-1C rats ( P < 0.05). The reduction in kidney function, and accumulation of renal fibrosis in 2K-1C rats were alleviated by nobiletin ( P < 0.05). Overexpression of AT 1 R and NADPH oxidase 4 (Nox4) protein in nonclipped kidney tissue was suppressed in the nobiletin-treated group ( P < 0.05). The elevations in oxidative stress parameters and the reductions in antioxidant enzymes were attenuated in 2K-1C rats treated with nobiletin ( P < 0.05). In summary, nobiletin had renin-angiotensin system inhibitory and antioxidant effects and attenuated LV dysfunction and remodelling via restoration of the AT 1 R/JAK/STAT pathway. Nobiletin also resolved renal damage that was related to modulation of the AT 1 R/Nox4 cascade in 2K-1C hypertension.