氯沙坦
医学
血管紧张素II
内科学
肾小球硬化
肾病
内分泌学
肾脏疾病
蛋白尿
内皮素受体
血管紧张素II受体拮抗剂
血管紧张素Ⅱ受体1型
促炎细胞因子
血管紧张素受体
肾
炎症
血压
受体
糖尿病
作者
Hiroki Nagasawa,Shoko Ueda,Hitoshi Suzuki,Celia Jenkinson,Yusuke Fukao,Maiko Nakayama,Tomoyuki Otsuka,Teruyuki Okuma,Wilmelenne Clapper,Kai Li,Mai Thanh Nguyen,Radko Komers,Yusuke Suzuki
摘要
Abstract Background The mechanism leading to the development of IgA nephropathy (IgAN) remains to be completely understood. Endothelin-1 (ET-1) as well as angiotensin II (AngII) promote glomerular injury, tubulointerstitial inflammation, and fibrosis leading to chronic kidney disease. Sparsentan, a dual endothelin angiotensin receptor antagonist (DEARA), recently received accelerated approval in United States for the reduction of proteinuria in adults with IgAN at high risk of disease progression. To elucidate the mechanisms by which sparsentan is efficacious in IgAN, we examined the effect of treatment in gddY mice, a spontaneous IgAN mouse model, versus the monoselective angiotensin II type 1 receptor (AT1R) antagonist, losartan, on the development of renal injury at doses resulting in similar blood pressure lowering. Methods Four-week-old gddY mice were given control chow, chow containing sparsentan, or drinking water containing losartan until 12 or 20 weeks old. Results Remarkably, the albumin:creatine ratio (ACR) was attenuated more rapidly and to a greater extent in mice treated with sparsentan than those treated with losartan. The decrease in ACR from baseline after 4 weeks of treatment correlated with beneficial effects of sparsentan on glomerulosclerosis and protection of podocytes and glycocalyx after 16 weeks of treatment across treatment groups; thus, sparsentan treatment delayed development of renal injury to a greater extent than losartan. Expression of mRNA for ET-1, ETAR, and AT1R and proinflammatory genes was upregulated in 12-week-old gddY mice and was prevented by sparsentan and losartan to a comparable extent. Conclusions The results of this study, and in light of the results of the phase 3 PROTECT trial, provide a novel perspective and understanding of the mechanisms by which sparsentan has a beneficial renoprotective effect against IgAN compared to AT1R antagonism alone.
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