Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi.
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
J Pharmacol Exp Ther. 2021 Apr;377(1):189-198. doi: 10.1124/jpet.120.000408. Epub 2021 Jan 7.
Previous studies identified a region on chromosome 1 associated with N-nitro-L-arginine methyl ester (L-NAME) hypertension-induced renal disease in fawn-hooded hypertensive (FHH) rats. This region contains a mutant -adducin () gene that impairs renal blood flow (RBF) autoregulation, but its contribution to renal injury is unknown. The present study evaluated the hypothesis that knockout (KO) of impairs the renal vasoconstrictor response to the blockade of nitric oxide synthase and enhances hypertension-induced renal injury after chronic administration of L-NAME plus a high-salt diet. The acute hemodynamic effect of L-NAME and its chronic effects on hypertension and renal injury were compared in FHH 1 (FHH 1) congenic rats (WT) expressing wild-type gene versus FHH 1 KO rats. RBF was well autoregulated in WT rats but impaired in KO rats. Acute administration of L-NAME (10 mg/kg) raised mean arterial pressure (MAP) similarly in both strains, but RBF and glomerular filtration rate (GFR) fell by 38% in WT versus 15% in KO rats. MAP increased similarly in both strains after chronic administration of L-NAME and a high-salt diet; however, proteinuria and renal injury were greater in KO rats than in WT rats. Surprisingly, RBF, GFR, and glomerular capillary pressure were 41%, 82%, and 13% higher in L-NAME-treated KO rats than in WT rats. Hypertensive KO rats exhibited greater loss of podocytes and glomerular nephrin expression and increased interstitial fibrosis than in WT rats. These findings indicate that loss of ADD3 promotes L-NAME-induced renal injury by altering renal hemodynamics and enhancing the transmission of pressure to glomeruli. SIGNIFICANCE STATEMENT: A mutation in the -adducin () gene in fawn-hooded hypertensive rats that impairs autoregulation of renal blood flow is in a region of rat chromosome 1 homologous to a locus on human chromosome 10 associated with diabetic nephropathy. The present results indicate that loss of ADD3 enhanced N-nitro-L-arginine methyl ester-induced hypertensive renal injury by altering the transmission of pressure to the glomerulus.
先前的研究确定了一个与 N-硝基-L-精氨酸甲酯 (L-NAME) 诱导的 fawn-hooded 高血压 (FHH) 大鼠肾脏疾病相关的染色体 1 区域。该区域包含一个突变的 - 内收蛋白 () 基因，该基因损害了肾血流量 (RBF) 的自动调节，但它对肾脏损伤的贡献尚不清楚。本研究评估了以下假设：敲除 () 会损害一氧化氮合酶阻断后的肾脏血管收缩反应，并增强慢性给予 L-NAME 加高盐饮食后高血压引起的肾脏损伤。在表达野生型 基因的 FHH 1 (FHH 1) 同基因大鼠 (WT) 与 FHH 1 KO 大鼠中比较了 L-NAME 的急性血流动力学效应及其对高血压和肾脏损伤的慢性影响。WT 大鼠的 RBF 自动调节良好，但 KO 大鼠的 RBF 自动调节受损。在两种品系中，急性给予 L-NAME (10mg/kg) 可使平均动脉压 (MAP) 相似升高，但 WT 大鼠的 RBF 和肾小球滤过率 (GFR) 下降 38%，而 KO 大鼠下降 15%。在两种品系中，慢性给予 L-NAME 和高盐饮食后 MAP 升高相似；然而，蛋白尿和肾脏损伤在 KO 大鼠中比 WT 大鼠更严重。令人惊讶的是，在 L-NAME 处理的 KO 大鼠中，RBF、GFR 和肾小球毛细血管压分别升高了 41%、82%和 13%。高血压 KO 大鼠比 WT 大鼠丢失更多的足细胞和肾小球 Nephrin 表达，并增加了间质纤维化。这些发现表明，缺失 ADD3 通过改变肾脏血流动力学和增强压力向肾小球的传递，促进了 L-NAME 诱导的肾脏损伤。 意义：在 fawn-hooded 高血压大鼠中，- 内收蛋白 () 基因的突变损害了肾血流量的自动调节，该基因位于大鼠染色体 1 与人类染色体 10 上与糖尿病肾病相关的一个区域同源。本研究结果表明，缺失 ADD3 通过改变压力向肾小球的传递，增强了 N-硝基-L-精氨酸甲酯诱导的高血压肾脏损伤。
