Mechanisms Underlying Increased TIMP2 and IGFBP7 Urinary Excretion in Experimental AKI
Mechanisms Underlying Increased TIMP2 and IGFBP7 Urinary Excretion in Experimental AKI
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DOI：
10.1681/asn.2018030265
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发表时间：
2018-08-01
影响因子：
13.6
通讯作者：
Zager, Richard A.
中科院分区：
文献类型：
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作者：
Johnson, Ali C. M.;Zager, Richard A.
背景最近的临床数据支持一种新的阿基生物标志物（NephroCheck）的效用/优越性，尿TIMP x IGFBP 7浓度的算术乘积。然而，其效用的病理生理基础仍然不明确defined.MethodsTo澄清这个问题，CD-1小鼠进行肾毒性（甘油，马来酸盐）或缺血性阿基。在伤后4和18小时测定尿TIMP 2/IGFBP 7浓度，并与尿白蛋白水平进行比较。通过测量肾皮质和/或髓质TIMP 2/IGFBP 7 mRNA（阿基诱导后4和18小时）评估基因转录。为了比较，评估了三种肾应激生物标志物（NGAL、血红素加氧酶1和p21）的mRNA。ELISA法检测肾皮质TIMP 2/IGFBP 7蛋白。近端小管特异性TIMP 2/IGFBP 7通过免疫组化进行了评估。ResultsEach阿基model induced prompt（4 hours）and marked urinary TIMP 2/IGFBP 7 increases without a increase in renal cortex concentrations.此外，TIMP 2/IGFBP 7 mRNA保持在正常水平。内毒素血症也未能增加TIMP 2/IGFBP 7 mRNA。相反，每个阿基模型引起大量NGAL、HO-1和p21 mRNA增加，证实发生了肾应激反应。尿白蛋白升高高达100倍，并与尿TIMP 2/IGFBP 7浓度强相关（r=0.87-0.91）。免疫组织化学显示，从受损的近端小管细胞中TIMP 2/IGFBP 7的损失进行性。竞争性抑制正常小鼠的内吞蛋白重吸收的三倍尿TIMP 2/IGFBP 7水平，确认这一途径的作用，在确定尿excretion. ConclusionsAKI诱导的尿TIMP 2/IGFBP 7升高是不是由于应激诱导的基因转录。相反，增加的过滤，减少肾小管重吸收，近端小管细胞TIMP 2/IGFBP 7尿渗漏似乎是最可能的机制。
BackgroundRecent clinical data support the utility/superiority of a new AKI biomarker (NephroCheck), the arithmetic product of urinary TIMP x IGFBP7 concentrations. However, the pathophysiologic basis for its utility remains ill defined.MethodsTo clarify this issue, CD-1 mice were subjected to either nephrotoxic (glycerol, maleate) or ischemic AKI. Urinary TIMP2/IGFBP7 concentrations were determined at 4 and 18 hours postinjury and compared with urinary albumin levels. Gene transcription was assessed by measuring renal cortical and/or medullary TIMP2/IGFBP7 mRNAs (4 and 18 hours after AKI induction). For comparison, the mRNAs of three renal stress biomarkers (NGAL, heme oxygenase 1, and p21) were assessed. Renal cortical TIMP2/IGFBP7 protein was gauged by ELISA. Proximal tubule-specific TIMP2/IGFBP7 was assessed by immunohistochemistry.ResultsEach AKI model induced prompt (4 hours) and marked urinary TIMP2/IGFBP7 increases without an increase in renal cortical concentrations. Furthermore, TIMP2/IGFBP7 mRNAs remained at normal levels. Endotoxemia also failed to increase TIMP2/IGFBP7 mRNAs. In contrast, each AKI model provoked massive NGAL, HO-1, and p21 mRNA increases, confirming that a renal stress response had occurred. Urinary albumin rose up to 100-fold and strongly correlated (r=0.87-0.91) with urinary TIMP2/IGFBP7 concentrations. Immunohistochemistry showed progressive TIMP2/IGFBP7 losses from injured proximal tubule cells. Competitive inhibition of endocytic protein reabsorption in normal mice tripled urinary TIMP2/IGFBP7 levels, confirming this pathway's role in determining urinary excretion.ConclusionsAKI-induced urinary TIMP2/IGFBP7 elevations are not due to stress-induced gene transcription. Rather, increased filtration, decreased tubule reabsorption, and proximal tubule cell TIMP2/IGFBP7 urinary leakage seem to be the most likely mechanisms.