Yin Wenqing, Naini Said Movahedi, Chen Guochun, Hentschel Dirk M, Humphreys Benjamin D, Bonventre Joseph V
Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts;
Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts; Harvard Stem Cell Institute, Cambridge, Massachusetts; and.
J Am Soc Nephrol. 2016 Jul;27(7):1943-57. doi: 10.1681/ASN.2015050500. Epub 2015 Nov 4.
Kidney injury molecule 1 (KIM-1), an epithelial phagocytic receptor, is markedly upregulated in the proximal tubule in various forms of acute and chronic kidney injury in humans and many other species. Whereas acute expression of KIM-1 has adaptive anti-inflammatory effects, chronic expression may be maladaptive in mice. Here, we characterized the zebrafish Kim family, consisting of Kim-1, Kim-3, and Kim-4. Kim-1 was markedly upregulated in kidney after gentamicin-induced injury and had conserved phagocytic activity in zebrafish. Both constitutive and tamoxifen-induced expression of Kim-1 in zebrafish kidney tubules resulted in loss of the tubule brush border, reduced GFR, pericardial edema, and increased mortality. Kim-1-induced kidney injury was associated with reduction of growth of adult fish. Kim-1 expression led to activation of the mammalian target of rapamycin (mTOR) pathway, and inhibition of this pathway with rapamycin increased survival. mTOR pathway inhibition in KIM-1-overexpressing transgenic mice also significantly ameliorated serum creatinine level, proteinuria, tubular injury, and kidney inflammation. In conclusion, persistent Kim-1 expression results in chronic kidney damage in zebrafish through a mechanism involving mTOR. This observation predicted the role of the mTOR pathway and the therapeutic efficacy of mTOR-targeted agents in KIM-1-mediated kidney injury and fibrosis in mice, demonstrating the utility of the Kim-1 renal tubule zebrafish models.
肾损伤分子1（KIM-1）是一种上皮吞噬受体，在人类和许多其他物种的各种急性和慢性肾损伤中，近端小管中的表达会显著上调。虽然KIM-1的急性表达具有适应性抗炎作用，但在小鼠中慢性表达可能具有适应不良性。在此，我们对斑马鱼的Kim家族进行了表征，该家族由Kim-1、Kim-3和Kim-4组成。庆大霉素诱导损伤后，Kim-1在肾脏中的表达显著上调，并且在斑马鱼中具有保守的吞噬活性。斑马鱼肾小管中Kim-1的组成型表达和他莫昔芬诱导的表达均导致肾小管刷状缘丧失、肾小球滤过率降低、心包水肿和死亡率增加。Kim-1诱导的肾损伤与成年鱼生长减缓有关。Kim-1的表达导致雷帕霉素哺乳动物靶标（mTOR）通路激活，用雷帕霉素抑制该通路可提高存活率。在过表达KIM-1的转基因小鼠中抑制mTOR通路也显著改善了血清肌酐水平、蛋白尿、肾小管损伤和肾脏炎症。总之，持续的Kim-1表达通过涉及mTOR的机制导致斑马鱼慢性肾损伤。这一观察结果预测了mTOR通路的作用以及mTOR靶向药物在小鼠KIM-1介导的肾损伤和纤维化中的治疗效果，证明了Kim-1肾小管斑马鱼模型的实用性。
