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

对9-25周龄自发性高血压大鼠(SHR)和Wistar-京都大鼠(WKY)麻醉后肾小球血流动力学和肾小管球球反馈(TGF)机制进行了研究。结果表明，9-10周龄自发性高血压大鼠(SHR)肾小球近端停流压(SEP)的最大降幅明显大于WKY(33比22%)，提示SHR肾小球近端停流压(SEP)是肾小球内压(PGC)的最大降幅。SHR的全身血压(SBP)高于WKY，肾血管阻力(RVR)大于WKY，肾血浆流量(RPF)低于WKY。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周龄、14-16周龄和23-25周龄自发性高血压患者中，零血流灌注下的SFP相似。腺苷A1受体拮抗剂(FK838，静脉注射)抑制SHR零灌流时的转化生长因子，增加SFP，使转化生长因子曲线上移。FK838增加了GFR、RPF和FENA，而SBP无变化。肾上腺髓质素(静脉注射)抑制SHR的转化生长因子至WKY的水平；SFP无变化，稳态时肾小管流量增加，提示转化生长因子曲线右移。肾上腺髓质素使SHR的SBP和RVR降低，GFR不变，RPF和FENA升高。结论：SHR在9~10周龄时有转化生长因子的激活，而PGC在9~25周龄时保持正常。A1拮抗剂或肾上腺髓质素抑制转化生长因子。前者通过扩张传入小动脉引起肾小球高血压和高滤过。然而，后者通过传入和传出血管扩张来维持PGC的正常。肾上腺髓质素可使转化生长因子正常化，诱导钠尿，降低SBP，从而可能阻止SHR肾小球硬化的发生和/或进展。

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.