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

在麻醉的9-25周龄自发性高血压大鼠（SHR）和WKY大鼠（WKY）上观察了肾小球血流动力学和肾小球反馈（TGF）机制。在9-10周龄时，SHR中Henle灌注环诱导的TGF-β 1表达显著高于WKY（33%对22%，在零灌注时SFP），表明SHR中TGF-β 1活性过高。SHR的体循环血压（SBP）高于WKY，肾血管阻力（RVR）大于WKY，肾血浆流量（RPF）小于WKY。然而，在14-16周龄时，未观察到SFP减少的差异（28%对28%）。在9-10、14-16和23-25周龄的SHR中，零灌注时的SFP相当。腺苷A1受体拮抗剂（FK 838，I. v.）在SHR中，在零灌注时抑制TGF和增加SFP，从而导致TGF曲线上移。FK 838增加GFR、RPF和FENa，而SBP保持不变。肾上腺髓质素（I. v.）将SHR的TGF抑制至WKY的水平;在零灌注时SFP不变，并且在稳态时肾小管流速增加，表明TGF曲线向右移动。肾上腺髓质素可使SHR收缩压和RVR下降，GFR不变，RPF和FENa升高，说明TGF在9-10周龄时处于激活状态，9-25周龄时Pgc保持正常。A1拮抗剂或肾上腺髓质素抑制TGF。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舒张保持Pgc正常。肾上腺髓质素使TGF正常化，诱导钠尿，并降低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.