Alström综合征1在肾小球血流动力学调节中的作用。

IF 3.7 2区 医学 Q1 PHYSIOLOGY
Sumit R Monu, D'Anna L Potter, Tang-Dong Liao, Keyona Nicole King, Pablo A Ortiz
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引用次数: 0

摘要

人类ALMS1基因的失活突变会导致Alström综合征,其特征是肥胖、胰岛素抵抗和肾功能障碍的早期发作。然而,ALMS1在肾功能和血流动力学中的作用尚不清楚。我们之前发现ALMS1在厚的上行肢体中表达,在那里它结合并降低Na+-K+-2Cl-协同转运蛋白的活性。我们假设ALMS1在致密斑细胞中表达,其缺失增强了大鼠的肾小管-肾小球反馈(TGF)并降低了肾小球滤过率(GFR)。为了验证这一点,研究了纯合ALMS1敲除(KO)和同窝出生的野生型达尔盐敏感大鼠。通过体内肾微穿刺测量,ALMS1 KO大鼠的TGF敏感性较高。使用共聚焦显微镜,我们证实了致密斑细胞中ALMS1的免疫标记(一氧化氮合酶1阳性),支持ALMS1在TGF调节中的作用。ALMS1 KO大鼠的基线肾小球毛细血管压较高,平均动脉压也较高。ALMS1 KO大鼠的肾间质静水压较低,这与Na+重吸收增加和高血压有关。ALMS1 KO大鼠的GFR降低。7周龄的ALMS1 KO大鼠没有蛋白尿,但在18至22周龄的ALSS1 KO大白鼠中存在蛋白尿。18周龄ALMS1-KO大鼠肾小球硬化指数较高。总之,ALMS1通过增强TGF敏感性参与肾小球血流动力学的控制,这可能有助于降低GFR。在ALMS1 KO大鼠中,TGF敏感性增加、肾小球毛细血管压升高和高血压可能导致肾小球损伤。这些是支持ALMS1在TGF和肾小球血流动力学中作用的第一批数据。NEW&NOTEWORTHY ALMS1是一种新型蛋白,参与调节肾小管-肾小球反馈(TGF)敏感性、肾小球毛细血管压和血压,其功能障碍可能降低肾功能并导致肾小球损伤。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Role of Alström syndrome 1 in the regulation of glomerular hemodynamics.

Inactivating mutations in the ALMS1 gene in humans cause Alström syndrome, characterized by the early onset of obesity, insulin resistance, and renal dysfunction. However, the role of ALMS1 in renal function and hemodynamics is unclear. We previously found that ALMS1 is expressed in thick ascending limbs, where it binds and decreases Na+-K+-2Cl- cotransporter activity. We hypothesized that ALMS1 is expressed in macula densa cells and that its deletion enhances tubuloglomerular feedback (TGF) and reduces glomerular filtration rate (GFR) in rats. To test this, homozygous ALMS1 knockout (KO) and littermate wild-type Dahl salt-sensitive rats were studied. TGF sensitivity was higher in ALMS1 KO rats as measured by in vivo renal micropuncture. Using confocal microscopy, we confirmed immunolabeling of ALMS1 in macula densa cells (nitric oxide synthase 1 positive), supporting a role for ALMS1 in TGF regulation. Baseline glomerular capillary pressure was higher in ALMS1 KO rats, as was mean arterial pressure. Renal interstitial hydrostatic pressure was lower in ALMS1 KO rats, which is linked to increased Na+ reabsorption and hypertension. GFR was reduced in ALMS1 KO rats. Seven-week-old ALMS1 KO rats were not proteinuric, but proteinuria was present in 18- to 22-wk-old ALMS1 KO rats. The glomerulosclerosis index was higher in 18-wk-old ALMS1 KO rats. In conclusion, ALMS1 is involved in the control of glomerular hemodynamics in part by enhancing TGF sensitivity, and this may contribute to decreased GFR. Increased TGF sensitivity, enhanced glomerular capillary pressure, and hypertension may lead to glomerular damage in ALMS1 KO rats. These are the first data supporting the role of ALMS1 in TGF and glomerular hemodynamics.NEW & NOTEWORTHY ALMS1 is a novel protein involved in regulating tubuloglomerular feedback (TGF) sensitivity, glomerular capillary pressure, and blood pressure, and its dysfunction may reduce renal function and cause glomerular damage.

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来源期刊
CiteScore
8.40
自引率
7.10%
发文量
154
审稿时长
2-4 weeks
期刊介绍: The American Journal of Physiology - Renal Physiology publishes original manuscripts on timely topics in both basic science and clinical research. Published articles address a broad range of subjects relating to the kidney and urinary tract, and may involve human or animal models, individual cell types, and isolated membrane systems. Also covered are the pathophysiological basis of renal disease processes, regulation of body fluids, and clinical research that provides mechanistic insights. Studies of renal function may be conducted using a wide range of approaches, such as biochemistry, immunology, genetics, mathematical modeling, molecular biology, as well as physiological and clinical methodologies.
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