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Mechanism of Initiation and Progression of Glomerular Sclerosis and its Prevention in Hypertensive Kidneys

高血压肾病肾小球硬化的发生、进展机制及防治

基本信息

批准号：
10670998
负责人：
TAKABATAKE Toshikazu
金额：
$ 1.73万
依托单位：
Shimane Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670998/
关键词：
hypertension microcirculation glomerular sclerosis kidney function intraglomerular pressure vasoactive substaces nephron rat

项目摘要

Glomerular hemodynamics and tubuloglomerular feedback (TGF) mechanism were evaluated in anesthetized 9-25-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY).Micropuncture experiments revealed that the maximal reduction of proximal stop-flow pressure (SEP), an index of intraglomerular pressure (Pgc), induced by loop of Henle perfusion was significantly larger in SHR than in WKY at 9-10 week old (33 vs. 22% of SFP at zero perfusion), indicating the hyperactivity of TGF in SHR. Systemic blood pressure (SBP) was higher, renal vascular resistance (RVR) was greater, and renal plasma flow (RPF) was less in SHR than in WKY. At 14-16 week old, however, the difference of SFP reduction was not observed (28 vs. 28%). SFP at zero perfusion was comparable among 9-10, 14-16, and 23-25-week-old SHR. Adenosine A1 receptor antagonist (FK838, I.v.) suppressed TGF and increased SFP at zero perfusion in SHR, thus induced an upwards shift of the TGF curve. FK838 increased GFR, RPF, and FENa, while SBP remained unaltered. Adrenomedullin (I.v.) suppressed TGF in SHR to the level in WKY ; the SFP at zero perfusion was unchanged and the tubular flow rate at the steady state increased, indicating a rightwards shift of the TGF curve. SBP and RVR were decreased, GFR unchanged, and RPF and FENa increased by adrenomedullin.In conclusion, TGF is activated in SHR at 9-10 week old, and Pgc remains normal in 9-25-week-old SHR. A1 antagonist or adrenomedullin suppresses TGF. The former induces the glomerular hypertension and hyperfiltration through the afferent arteriolar vasodilatation. The latter, however, keeps Pgc normal through both afferent and efferent vasodilatation. Adrenomedullin normalizes TGF, induces natriuresis, and lowers SBP, and thereby may prevent the initiation and/or the progression of the glomerular sclerosis in SHR.

观察麻醉9-25周龄自发性高血压大鼠（SHR）和Wistar-Kyoto大鼠（WKY）的肾小球血流动力学和小管肾小球反馈（TGF）机制。微穿刺实验显示，在9-10周龄时，Henle灌注循环诱导的近端止流压（SEP），肾小球内压（Pgc）指标，SHR组的最大降幅明显大于WKY组（33% vs. 22%），表明TGF在SHR中的高活性。SHR组全身血压（SBP）较高，肾血管阻力（RVR）较大，肾血浆流量（RPF）低于WKY组。然而，在14-16周龄时，没有观察到SFP减少的差异（28%对28%）。在9-10周、14-16周和23-25周SHR中，零灌注时的SFP具有可比性。腺苷A1受体拮抗剂（FK838， I.v）在SHR中零灌注时抑制TGF，增加SFP，从而诱导TGF曲线向上移动。FK838增加GFR、RPF和FENa，而收缩压保持不变。肾上腺髓质素（肾上腺素）抑制SHR中TGF至WKY水平；零灌注时的SFP不变，稳态时的管状流速增加，说明TGF曲线向右移动。肾上腺髓质素使收缩压和RVR降低，GFR不变，RPF和FENa升高。综上所述，9-10周龄SHR中TGF被激活，9-25周龄SHR中Pgc保持正常。A1拮抗剂或肾上腺髓质素抑制TGF。前者通过传入小动脉血管扩张诱导肾小球高血压和超滤过。然而，后者通过传入和传出血管扩张保持Pgc正常。肾上腺髓质素使TGF正常化，诱导尿钠，降低收缩压，从而可能阻止SHR肾小球硬化的发生和/或进展。