Ravichandran Kameswaran, Ozkok Abdullah, Wang Qian, Mullick Adam E, Edelstein Charles L
Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, Colorado; and.
ISIS Pharmaceuticals, Carlsbad, California.
Am J Physiol Renal Physiol. 2015 Feb 15;308(4):F349-57. doi: 10.1152/ajprenal.00478.2014. Epub 2014 Dec 23.
Renal cyst enlargement is associated with the activation of both the circulating and intrarenal renin-angiotensin systems. Angiotensinogen (AGT) is the substrate for renin. The aim of the present study was to determine the effect of AGT inhibition on renal cyst enlargement. An AGT antisense oligonucleotide (ASO) that selectively inhibits AGT mRNA was injected once weekly in PKD2WS25 mice [an orthologous model of human autosmal dominant polycystic kidney disease (PKD) involving mutation of the Pkd2 gene] from 4 to 16 wk of age. The AGT ASO resulted in a 40% decrease in AGT RNA in the kidney, a 60% decrease in AGT RNA in the liver, and a significant decrease in AGT protein in the kidney and serum. The AGT ASO resulted in a significant decrease in kidney size, cyst volume density, and blood urea nitrogen. The AGT ASO resulted in a significant decrease in transforming growth factor-β and interstitial fibrosis in the kidney. Mice treated with the AGT ASO had a significant decrease in proinflammatory cytokines [chemokine (C-X-C motif) ligand (CXCL)1 and IL-12] in the kidney. Cluster of differentiation (CD)36 is a scavenger receptor found on tubular cells that can activate the renin-angiotensin system. Administration of a CD36 ASO had no effect on PKD and kidney function, suggesting that the effect of the AGT ASO is independent of CD36. In summary, AGT inhibition resulted in significant decreases in kidney size and cyst volume and an improvement in kidney function in PKD mice. The AGT ASO resulted in a decrease in transforming growth factor-β, interstitial fibrosis, and the proinflammatory cytokines CXCL1 and IL-12 in the kidney.
肾囊肿增大与循环及肾内肾素 - 血管紧张素系统的激活有关。血管紧张素原（AGT）是肾素的底物。本研究的目的是确定AGT抑制对肾囊肿增大的影响。从4至16周龄起，每周一次向PKD2WS25小鼠[一种涉及Pkd2基因突变的人类常染色体显性多囊肾病（PKD）的直系同源模型]注射选择性抑制AGT mRNA的AGT反义寡核苷酸（ASO）。AGT ASO使肾脏中AGT RNA减少40%，肝脏中AGT RNA减少60%，并且使肾脏和血清中的AGT蛋白显著减少。AGT ASO使肾脏大小、囊肿体积密度和血尿素氮显著降低。AGT ASO使肾脏中转化生长因子 -β和间质纤维化显著减少。用AGT ASO处理的小鼠肾脏中的促炎细胞因子[趋化因子（C - X - C基序）配体（CXCL）1和IL - 12]显著减少。分化簇（CD）36是一种在肾小管细胞上发现的清道夫受体，可激活肾素 - 血管紧张素系统。给予CD36 ASO对PKD和肾功能无影响，这表明AGT ASO的作用独立于CD36。总之，AGT抑制导致PKD小鼠的肾脏大小和囊肿体积显著减小以及肾功能改善。AGT ASO使肾脏中的转化生长因子 -β、间质纤维化以及促炎细胞因子CXCL1和IL - 12减少。
