Rodriguez Ruben, Escobedo Benny, Lee Andrew Y, Thorwald Max, Godoy-Lugo Jose A, Nakano Daisuke, Nishiyama Akira, Parkes David G, Ortiz Rudy M
Department of Molecular & Cellular Biology, University of California Merced, Merced, CA, USA.
Department of Pharmacology, Kagawa University Medical School, Kagawa, Japan.
Clin Exp Pharmacol Physiol. 2020 Mar;47(3):422-431. doi: 10.1111/1440-1681.13206. Epub 2019 Dec 5.
Insulin resistance increases renal oxidant production by upregulating NADPH oxidase 4 (Nox4) expression contributing to oxidative damage and ultimately albuminuria. Inhibition of the renin-angiotensin system (RAS) and activation of glucagon-like peptide-1 (GLP-1) receptor signalling may reverse this effect. However, whether angiotensin receptor type 1 (AT1) blockade and GLP-1 receptor activation improve oxidative damage and albuminuria through different mechanisms is not known. Using insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats, we tested the hypothesis that simultaneous blockade of AT1 and activation of GLP-1r additively decrease oxidative damage and urinary albumin excretion (U V) in the following groups: (a) untreated, lean LETO (n = 7), (b) untreated, obese OLETF (n = 9), (c) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d; n = 9), (d) OLETF + GLP-1 mimetic (EXE; 10 µg exenatide/kg/d; n = 7) and (e) OLETF + ARB +exenatide (Combo; n = 6). Mean kidney Nox4 protein expression and nitrotyrosine (NT) levels were 30% and 46% greater, respectively, in OLETF compared with LETO. Conversely, Nox4 protein expression and NT were reduced to LETO levels in ARB and EXE, and Combo reduced Nox4, NT and 4-hydroxy-2-nonenal levels by 21%, 27% and 27%, respectively. At baseline, U V was nearly double in OLETF compared with LETO and increased to nearly 10-fold greater levels by the end of the study. Whereas ARB (45%) and EXE (55%) individually reduced U V, the combination completely ameliorated the albuminuria. Collectively, these data suggest that AT1 blockade and GLP-1 receptor activation reduce renal oxidative damage similarly during insulin resistance, whereas targeting both signalling pathways provides added benefit in restoring and/or further ameliorating albuminuria in a model of diet-induced obesity.
胰岛素抵抗通过上调NADPH氧化酶4（Nox4）的表达增加肾脏氧化剂的产生，导致氧化损伤并最终引发蛋白尿。抑制肾素-血管紧张素系统（RAS）和激活胰高血糖素样肽-1（GLP-1）受体信号传导可能会逆转这种效应。然而，1型血管紧张素受体（AT1）阻断和GLP-1受体激活是否通过不同机制改善氧化损伤和蛋白尿尚不清楚。我们使用胰岛素抵抗的大冢长-艾维-德岛肥胖（OLETF）大鼠，在以下几组中检验了同时阻断AT1和激活GLP-1受体可累加性降低氧化损伤和尿白蛋白排泄（U V）的假设：（a）未治疗的瘦型LETO大鼠（n = 7），（b）未治疗的肥胖OLETF大鼠（n = 9），（c）OLETF +血管紧张素受体阻滞剂（ARB；奥美沙坦10 mg/kg/d；n = 9），（d）OLETF + GLP-1模拟物（EXE；艾塞那肽10 μg/kg/d；n = 7），以及（e）OLETF + ARB +艾塞那肽（联合组；n = 6）。与LETO相比，OLETF大鼠肾脏Nox4蛋白表达和硝基酪氨酸（NT）水平分别平均高30%和46%。相反，ARB组和EXE组的Nox4蛋白表达和NT水平降至LETO大鼠的水平，联合组使Nox4、NT和4-羟基-2-壬烯醛水平分别降低了21%、27%和27%。在基线时，与LETO相比，OLETF大鼠的U V几乎翻倍，到研究结束时增加到近10倍。虽然ARB（45%）和EXE（55%）单独降低了U V，但联合用药完全改善了蛋白尿。总体而言，这些数据表明，在胰岛素抵抗期间，AT1阻断和GLP-1受体激活对降低肾脏氧化损伤的作用相似，而针对这两种信号通路在饮食诱导肥胖模型中恢复和/或进一步改善蛋白尿方面具有额外益处。
