Combining Neprilysin Inhibitor With AT(2)R Agonist Is Superior to Combination With AT(1)R Blocker in Providing Reno-Protection in Obese Rats.
Combining Neprilysin Inhibitor With AT(2)R Agonist Is Superior to Combination With AT(1)R Blocker in Providing Reno-Protection in Obese Rats.
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DOI：
10.3389/fphar.2021.778953
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发表时间：
2021
影响因子：
5.6
通讯作者：
Hussain T
中科院分区：
文献类型：
--
作者：
Gray EA;Patel SN;Doris PA;Hussain T
已知脑啡肽酶抑制剂沙库巴曲和血管紧张素 II 1 型受体阻滞剂缬沙坦联合治疗的临床使用与白蛋白尿有关。蛋白尿既是肾损伤的危险因素，也是肾损伤的指标。我们实验室的早期工作报道，血管紧张素 II 2 型受体化合物 21 (C21) 的激动剂可预防蛋白尿、白蛋白尿，并且对喂食高盐饮食 (HSD) 的肥胖 Zucker 大鼠具有肾脏保护作用。因此，我们假设与 sacubitril/valsartan 相比，sacubitril/C21 组合可提供更好的肾病保护作用。 10-11 周龄的雄性肥胖 Zucker 大鼠每天接受赋形剂、沙库巴曲 + C21 或沙库巴曲 + 缬沙坦治疗，同时喂食 HSD，持续 16 天。 HSD 喂养会导致肾功能障碍，表现为尿蛋白、骨桥蛋白和胱抑素 C 显着增加。HSD 喂养降低血浆胱抑素 C 和肌酐浓度，提示超滤，而这不受任何治疗的影响。与沙库巴曲/缬沙坦不同，与单独使用 HSD 相比，沙库巴曲/C21 治疗可显着降低蛋白尿、白蛋白尿、去氧肾上腺素表达和肾脏重量，且与超滤无关。此外，沙库巴曲/缬沙坦治疗可增加血浆肾素，但不能阻止 HSD 诱导的肾血管紧张素 II 增加，而沙库巴曲/C21 则完全阻止这些变化。总之，这项研究表明，在高盐喂养的肥胖 Zucker 大鼠中，与 sacubitril/valsartan 治疗相比，sacubitril/C21 提供了更好的肾病保护作用。
Clinical use of the combination therapy of the neprilysin inhibitor sacubitril and angiotensin II type 1 receptor blocker valsartan is known to be associated with albuminuria. Albuminuria is both a risk factor for and an indicator of kidney injury. Earlier work from our laboratory reported that the agonist of angiotensin II type 2 receptor Compound 21 (C21) prevents proteinuria, albuminuria, and is reno-protective in obese Zucker rats fed high salt diet (HSD). Thus, we hypothesized that sacubitril/C21 combination provides superior reno-protection compared to sacubitril/valsartan. Male obese Zucker rats 10–11 weeks old were treated daily with vehicle, sacubitril + C21, or sacubitril + valsartan while fed HSD for 16 days. HSD-feeding caused kidney dysfunction, evident by significant increases in urinary protein, osteopontin, and cystatin C. HSD-feeding lowered plasma cystatin C and creatinine concentrations suggestive of hyperfiltration, which was not affected by either treatment. Unlike sacubitril/valsartan, sacubitril/C21 treatment significantly decreases proteinuria, albuminuria, the expression of nephrin, and kidney weight, independent of hyperfiltration, compared with HSD alone. Moreover, sacubitril/valsartan therapy increased plasma renin and did not prevent HSD-induced increases in renal angiotensin II, while sacubitril/C21 completely prevented these changes. Together, this study suggests that sacubitril/C21 afforded superior reno-protection compared to sacubitril/valsartan therapy in high salt-fed obese Zucker rats.
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DOI：
10.1152/ajprenal.00145.2002
发表时间：
2002-11-01
影响因子：
4.2
作者：
Armando, I;Jezova, M;Saavedra, JM
通讯作者：
Saavedra, JM
影响因子：
2.5
作者：
Clavant, Steven P.;Forbes, Josephine M.;Comper, Wayne D.
通讯作者：
Comper, Wayne D.
影响因子：
7.7
作者：
Fischer, JW;Tschöpe, C;Unger, T
通讯作者：
Unger, T
影响因子：
8.3
作者：
Hilliard, Lucinda M.;Chow, Charis L. E.;Denton, Kate M.
通讯作者：
Denton, Kate M.
影响因子：
8.3
作者：
Hilliard, Lucinda M.;Jones, Emma S.;Denton, Kate M.
通讯作者：
Denton, Kate M.