Pleasant LaTawnya, Ma Qing, Devarajan Mahima, Parameswaran Priyanka, Drake Keri, Siroky Brian, Shay-Winkler Kritton, Robbins Jeffrey, Devarajan Prasad
Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; and.
Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Am J Physiol Renal Physiol. 2017 Sep 1;313(3):F699-F705. doi: 10.1152/ajprenal.00505.2016. Epub 2017 Jul 5.
The early events that signal renal dysfunction in presymptomatic heart failure are unclear. We tested the hypothesis that functional and mechanistic changes occur in the kidney that precede the development of symptomatic heart failure. We employed a transgenic mouse model with cardiomyocyte-specific overexpression of mutant α-B-crystallin that develops slowly progressive cardiomyopathy. Presymptomatic transgenic mice displayed an increase in serum creatinine (1.17 ± 0.34 vs. wild type 0.65 ± 0.16 mg/dl, < 0.05) and in urinary neutrophil gelatinase-associated lipocalin (NGAL; 278.92 ± 176.24 vs. wild type 49.11 ± 22.79 ng/ml, < 0.05) but no renal fibrosis. Presymptomatic transgenic mouse kidneys exhibited a twofold upregulation of the gene, marked overexpression of renin protein in the tubules, and a worsened response to ischemia-reperfusion injury based on serum creatinine (2.77 ± 0.66 in transgenic mice vs. 2.01 ± 0.58 mg/dl in wild type, < 0.05), urine NGAL (9,198.79 ± 3,799.52 in transgenic mice vs. 3,252.94 ± 2,420.36 ng/ml in wild type, < 0.05), tubule dilation score (3.4 ± 0.5 in transgenic mice vs. 2.6 ± 0.5 in wild type, < 0.05), tubule cast score (3.2 ± 0.4 in transgenic mice vs. 2.5 ± 0.5 in wild type, < 0.05), and TdT-mediated dUTP nick-end labeling (TUNEL)-positive nuclei (10.1 ± 2.1 in the transgenic group vs. 5.7 ± 1.6 per 100 cells counted in wild type, < 0.01). Our findings indicate functional renal impairment, urinary biomarker elevations, and induction of renin gene and protein expression in the kidney that occur in early presymptomatic heart failure, which increase the susceptibility to subsequent acute kidney injury.
在无症状性心力衰竭中预示肾功能障碍的早期事件尚不清楚。我们检验了这样一个假说，即在有症状性心力衰竭发生之前，肾脏会发生功能和机制上的改变。我们采用了一种转基因小鼠模型，其心肌细胞特异性过表达突变型α-B-晶状体蛋白，会发展为缓慢进行性心肌病。无症状的转基因小鼠血清肌酐升高（1.17±0.34 vs.野生型0.65±0.16 mg/dl，<0.05），尿中性粒细胞明胶酶相关脂质运载蛋白（NGAL）升高（278.92±176.24 vs.野生型49.11±22.79 ng/ml，<0.05），但没有肾纤维化。无症状转基因小鼠肾脏的该基因上调两倍，肾小管中肾素蛋白明显过表达，基于血清肌酐（转基因小鼠为2.77±0.66 vs.野生型2.01±0.58 mg/dl，<0.05）、尿NGAL（转基因小鼠为9198.79±3799.52 vs.野生型3252.94±2420.36 ng/ml，<0.05）、肾小管扩张评分（转基因小鼠为3.4±0.5 vs.野生型2.6±0.5，<0.05）、肾小管铸型评分（转基因小鼠为3.2±0.4 vs.野生型2.5±0.5，<0.05）以及末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）阳性细胞核（转基因组每100个细胞计数为10.1±2.1 vs.野生型为5.7±1.6，<0.01），其对缺血再灌注损伤的反应更差。我们的研究结果表明，在无症状性心力衰竭早期会出现功能性肾损伤、尿生物标志物升高以及肾脏中肾素基因和蛋白表达的诱导，这会增加随后发生急性肾损伤的易感性。
