Wong Muh Geot, Suzuki Yusuke, Tanifuji Chiaki, Akiba Hisaya, Okumura Ko, Sugaya Takeshi, Yamamoto Tokunori, Horikoshi Satoshi, Tan Si Yen, Pollock Carol, Tomino Yasuhiko
Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 1138421, Japan.
J Am Soc Nephrol. 2008 Feb;19(2):290-7. doi: 10.1681/ASN.2007020226. Epub 2007 Dec 19.
Proteinuria is a key factor in the progression of tubulointerstitial injury. Recently, tubular ischemia as a result of loss of peritubular capillaries has been identified as another major contributor to disease progression, but the relative contribution of these insults on tubulointerstitial damage is unknown. Anti–glomerular basement membrane glomerulonephritis was induced in wild-type (WT) and Fc receptor knockout (FcRKO) mice, which have been shown to be relatively protected against glomerular endothelial injury. Despite comparable degrees of proteinuria, WT mice developed significantly worse renal function than FcRKO mice, along with higher expression of both type I collagen and kidney injury molecule-1 (a sensitive marker of acute tubular injury) by real-time PCR and immunohistochemistry. In addition, compared with FcRKO mice, WT mice exhibited a greater decrease in peritubular red blood cell velocity by intravital videomicroscopy and a marked increase of tissue hypoxia. , kidney injury molecule-1 expression increased in cultured mouse proximal tubular epithelial cells in response to cellular stresses, including hypoxia, starvation, and exposure to excessive protein; therefore, it is suggested that hypoxic insults more strongly influence tubulointerstitial damage than proteinuria alone in models of subacute renal disease.
蛋白尿是肾小管间质损伤进展的关键因素。最近，由于肾小管周围毛细血管丧失导致的肾小管缺血已被确定为疾病进展的另一个主要因素，但这些损伤对肾小管间质损伤的相对贡献尚不清楚。在野生型（WT）和Fc受体敲除（FcRKO）小鼠中诱导抗肾小球基底膜肾小球肾炎，已证明它们对肾小球内皮损伤具有相对保护作用。尽管蛋白尿程度相当，但WT小鼠的肾功能明显比FcRKO小鼠差，通过实时PCR和免疫组织化学检测，I型胶原蛋白和肾损伤分子-1（急性肾小管损伤的敏感标志物）的表达也更高。此外，与FcRKO小鼠相比，WT小鼠通过活体视频显微镜观察显示肾小管周围红细胞速度下降更大，组织缺氧明显增加。肾损伤分子-1的表达在培养的小鼠近端肾小管上皮细胞中因细胞应激（包括缺氧、饥饿和暴露于过量蛋白质）而增加；因此，提示在亚急性肾病模型中，缺氧损伤比单独的蛋白尿更强烈地影响肾小管间质损伤。
