Prevention of acute ischemic renal failure by targeted delivery of growth factors to the proximal tubule in transgenic mice:: The efficacy of parathyroid hormone-related protein and hepatocyte growth factor
Prevention of acute ischemic renal failure by targeted delivery of growth factors to the proximal tubule in transgenic mice:: The efficacy of parathyroid hormone-related protein and hepatocyte growth factor
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DOI：
10.1097/01.asn.0000102470.12285.c6
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发表时间：
2004-01-01
影响因子：
13.6
通讯作者：
Garcia-Ocaña, A
中科院分区：
文献类型：
--
作者：
Fiaschi-Taesch, NM;Santos, S;Garcia-Ocaña, A
急性肾功能衰竭(ARF)的治疗将通过确定加速肾脏损伤恢复的因素而得到加强。甲状旁腺激素相关蛋白(PTHrP)和肝细胞生长因子(HGF)可刺激近端肾单位来源的细胞增殖。为了研究这两种因子在ARF中的病理生理作用和治疗潜力，我们建立了在γ-谷氨酰转肽酶-I启动子的指导下在近端小管高表达PTHrP或HGF的转基因小鼠。这些小鼠表现出(1)各自转基因在肾脏中的丰富表达；(2)与对照仔鼠相比，近端小管中PTHI型受体和HGF受体(c-MET)的表达水平相似；(3)基础条件下肾脏的形态、功能和肾小管细胞增殖正常。然而，与对照组相比，当诱导急性缺血性肾损伤时，HGF过表达的小鼠的肾功能迅速而显著地恢复。此外，缺血48h后，高表达HGF的转基因小鼠肾小管上皮细胞增殖率为对照组的4倍，凋亡性肾小管上皮细胞的凋亡率为对照组的3倍。相反，PTHrP过表达的小鼠对缺血或叶酸诱导的肾损伤的反应与对照组小鼠相似。这些研究表明，PTHrP在小鼠近端肾单位的过度表达似乎不能提供对急性肾损伤的保护。与之形成鲜明对比的是，在正常情况下，HGF的过度表达对缺血诱导的ARF有显著的保护作用，而不会对肾脏的生理产生任何明显的影响。这些研究表明，当HGF特异性地定位于近端小管时，可能在提供对缺血诱导的肾功能衰竭的保护方面具有治疗潜力。
Treatment of acute renal failure (ARF) would be enhanced by identification of factors that accelerate renal recovery from injury. Parathyroid hormone-related protein (PTHrP) and hepatocyte growth factor (HGF) have been shown to stimulate proliferation in proximal nephron-derived cells. For studying the pathophysiologic roles and therapeutic potential of these two factors in ARF, transgenic mice overexpressing PTHrP or HGF in the proximal tubule under the direction of the gamma-glutamyl transpeptidase-I promoter were developed. These mice display (1) abundant expression of the respective transgenes in the kidney; (2) similar PTH type I receptor and HGF receptor (c-met) expression levels in the proximal tubule compared with control littermates; and (3) normal renal morphology, function, and tubule cell proliferation under basal conditions. However, in contrast to control mice, when acute ischemic renal injury was induced, renal function rapidly and dramatically recovered in HGF-overexpressing mice. In addition, 48 h after ischemia, HGF-overexpressing transgenic mice displayed a fourfold increase in tubule cell proliferation and a threefold decrease in apoptotic tubule cell death compared with control mice. In contrast, PTHrP-overexpressing mice responded to either ischemic or folic acid-induced renal damage similarly to control mice. These studies demonstrate that overexpression of PTHrP in the proximal nephron of mice does not seem to provide protection against acute renal injury. In marked contrast, HGF overexpression results in dramatic protection from ischemia-induced ARF, without inducing any apparent alteration in the physiology of the kidney under normal conditions. These studies suggest that HGF, when targeted specifically to the proximal tubule, may have therapeutic potential in providing protection against ischemia-induced renal failure.