Contributions of angiotensin II and tumor necrosis factor-α to the development of renal fibrosis
Contributions of angiotensin II and tumor necrosis factor-α to the development of renal fibrosis
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DOI：
10.1152/ajprenal.2001.280.5.f777
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发表时间：
2001-05-01
影响因子：
4.2
通讯作者：
Klahr, S
中科院分区：
文献类型：
--
作者：
Guo, GJ;Morrissey, J;Klahr, S
血管紧张素II上调单侧输尿管梗阻（UUO）大鼠肾脏肿瘤坏死因子-α（TNF-α）在UUO小鼠模型中，我们发现当TNF-α受体TNFR 1被功能性敲除时，肾小管间质纤维化变钝。在这项研究中，我们使用UUO突变小鼠，其中血管紧张素II受体AT（1a）或TNF-α受体TNFR 1和TNFR 2被敲除，以阐明两个系统之间的相互作用。通过用血管紧张素转换酶抑制剂依那普利治疗TNFR 1/TNFR 2双敲除（KO）小鼠，评估这两种系统对肾纤维化的贡献。在C57 BI/6野生型小鼠中增加的间质体积（V（vint））在AT 1a KO中从32.8 +/- 4.0降低至21.0 +/- 3.7%（P< 0.005）或在TNFR 1/TNFR 2 KO中降低至22.3 +/- 2.1%（P< 0.005）。与未治疗相比，依那普利使TNFR 1/TNFR 2 KO的Vvint进一步降低至15.2 ± 3.7%（P< 0.01）。与野生型小鼠相比，在AT（1a）或TNFR 1/TNFR 2 KO小鼠中，UUO肾脏中TNF- mRNA和转化生长因子-β 1（TGF-β 1）mRNA的诱导明显减弱。用依那普利治疗TNFR 1/TNFR 2基因敲除小鼠后，TNF-α和TGF-β 1 mRNA及其蛋白质均降至接近正常水平。此外，AT（1a）或TNFR 1/TNFR 2 KO小鼠的α-平滑肌肌动蛋白表达和肌成纤维细胞增殖受到显著抑制，并且在依那普利治疗的TNFR 1/TNFR 2 KO小鼠中受到进一步抑制。使血管紧张素II或TNF-α系统失能分别导致纤维化的部分钝化。通过使用遗传和药理学手段的组合使这两个系统失能，进一步抑制了阻塞性肾病中的间质纤维化和小管萎缩。
Angiotensin II upregulates tumor necrosis factor-alpha (TNF-alpha) in the rat kidney with unilateral ureteral obstruction (UUO). In a mouse model of UUO, we found that tubulointerstitial fibrosis is blunted when the TNF-alpha receptor, TNFR1, is functionally knocked out. In this study, we used mutant mice with UUO in which the angiotensin II receptor AT(1a) or the TNF-alpha receptors TNFR1 and TNFR2 were knocked out to elucidate interactions between the two systems. The contribution of both systems to renal fibrosis was assessed by treating TNFR1/TNFR2-double knockout (KO) mice with an angiotensin-converting enzyme inhibitor, enalapril. The increased interstitial volume (V(vint)) in the C57BI/6 wild-type mouse was decreased in the AT1a KO from 32.8 +/- 4.0 to 21.0 +/- 3.7% (P< 0.005) or in the TNFR1/TNFR2 KO to 22.3 +/- 2.1% (P< 0.005). The Vvint of the TNFR1/TNFR2 KO was further decreased to 15.2 +/- 3.7% (P< 0.01) by enalapril compared with no treatment. The induction of TNF- mRNA and transforming growth factor-beta1 (TGF-beta1) mRNA in the kidney with UUO was significantly blunted in the AT(1a) or TNFR1/TNFR2 KO mice compared with the wild-type mice. Treatment of the TNFR1/TNFR2 KO mouse with enalapril reduced both TNF-alpha and TGF-beta1 mRNA and their proteins to near normal levels. Also, alpha -smooth muscle actin expression and myofibroblast proliferation were significantly inhibited in the AT(1a) or TNFR1/TNFR2 KO mice, and they were further inhibited in enalapril-treated TNFR1/TNFR2 KO mice. Incapacitating the angiotensin II or the TNF-alpha systems individually leads to partial blunting of fibrosis. Incapacitating both systems, by using a combination of genetic and pharmacological means, further inhibited interstitial fibrosis and tubule atrophy in obstructive nephropathy.