Danielson Lee A, Welford Angela, Harris Alexis
University of New Mexico, MSC09 5250, Albuquerque, NM 87131-0001, USA.
J Am Soc Nephrol. 2006 May;17(5):1325-33. doi: 10.1681/ASN.2005121307. Epub 2006 Apr 5.
Administration of recombinant human relaxin (rhRLX) to conscious, chronically instrumented rats increases GFR and effective renal plasma flow (ERPF) and decreases effective renal vascular resistance (ERVR) with no significant change in mean arterial pressure. The Munich Wistar albino rat shows progressive chronic nephrosis with age and therefore was used to determine the functional and histologic consequences of rhRLX on matrix remodeling in the kidney of older rats. RLX-infused rats showed increased GFR and ERPF with decreased ERVR. Furthermore, in a double-blinded examination, the renal histology showed a significant decrease in glomerular and tubular collagen deposition in the rhRLX-infused aged rats. During short-term rhRLX administration (24 h), gelatinase activity was found to be essential for renal vasodilation and hyperfiltration. Surprisingly, after 20 d, improved renal function was insensitive to the inhibition of gelatinase activity, suggesting that collagen degradation in these rats had permanently altered the matrix of the renal vasculature. In conclusion, long-term administration of rhRLX improves renal function and ameliorates renal pathology in an aging rat model. The biphasic action of rhRLX on the kidney indicates that, acutely, the vessels dilate, causing increased filtration and renal blood flow with decreased vascular resistance as a result of upregulation of gelatinase activity. Subsequently, the renal vessels undergo alteration in supporting matrix, showing increased blood supply even in the face of acute matrix metalloproteinase inhibition, most likely as a result of the inhibitory properties of RLX on collagen production or increased collagen breakdown.
给清醒的、长期植入仪器的大鼠注射重组人松弛素（rhRLX），可增加肾小球滤过率（GFR）和有效肾血浆流量（ERPF），并降低有效肾血管阻力（ERVR），而平均动脉压无显著变化。慕尼黑Wistar白化大鼠会随着年龄增长出现进行性慢性肾病，因此被用于确定rhRLX对老年大鼠肾脏基质重塑的功能和组织学影响。注射RLX的大鼠GFR和ERPF增加，ERVR降低。此外，在双盲检查中，肾脏组织学显示，注射rhRLX的老年大鼠肾小球和肾小管胶原沉积显著减少。在短期注射rhRLX（24小时）期间，发现明胶酶活性对于肾血管舒张和超滤至关重要。令人惊讶的是，20天后，改善的肾功能对明胶酶活性抑制不敏感，这表明这些大鼠的胶原降解已永久性改变了肾血管的基质。总之，在衰老大鼠模型中，长期注射rhRLX可改善肾功能并减轻肾脏病理变化。rhRLX对肾脏的双相作用表明，急性时，血管舒张，导致滤过增加和肾血流量增加，血管阻力降低，这是由于明胶酶活性上调所致。随后，肾血管的支持基质发生改变，即使在急性基质金属蛋白酶抑制的情况下，血液供应仍增加，这很可能是由于RLX对胶原产生的抑制作用或胶原分解增加所致。
