Reduced Kruppel-Like Factor 2 Aggravates Glomerular Endothelial Cell Injury and Kidney Disease in Mice with Unilateral Nephrectomy

被引:35
作者
Zhong, Fang [1 ,3 ]
Mallipattu, Sandeep K. [4 ]
Estrada, Chelsea [4 ]
Menon, Madhav [1 ]
Salem, Fadi [2 ]
Jain, Mukesh K. [5 ]
Chen, Hongyu [3 ]
Wang, Yongjun [3 ]
Lee, Kyung [1 ]
He, John C. [1 ,6 ]
机构
[1] Icahn Sch Med Mt Sinai, Dept Med Nephrol, New York, NY USA
[2] Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY USA
[3] Zhejiang Chinese Med Univ, Hang Zhou Hosp Tradit Chinese Med, Dept Nephrol, Hangzhou, Zhejiang, Peoples R China
[4] SUNY Stony Brook, Dept Med, Div Nephrol, Stony Brook, NY USA
[5] Case Western Reserve Univ, Case Cardiovasc Inst Res Inst, Dept Med, Cleveland, OH USA
[6] James J Peters Vet Affairs Med Ctr, Renal Sect, Bronx, NY USA
关键词
RENAL HEMODYNAMIC-RESPONSE; PROINFLAMMATORY ACTIVATION; TRANSCRIPTION FACTORS; NITRIC-OXIDE; KLF2; EXPRESSION; REGULATOR; DIFFERENTIATION; DEFICIENCY; PODOCYTES;
D O I
10.1016/j.ajpath.2016.03.018
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
Loss of functional nephrons induces compensatory glomerular hyperfiltration and hypertrophy, leading to the progression of chronic kidney disease. Kruppel-like factor 2 (KLF2), a shear-stress inducible transcription factor, confers protection against endothelial injury. Because glomerular hyperfiltration is associated with shear stress, we hypothesized that KLF2 may be an important factor in the compensatory response to unilateral nephrectomy (UNX). To test this hypothesis, endothelial cell specific Klf2 heterozygous knockout mice (KO) and their wild-type Littermate control (WT) underwent either UNX or sham-operation. WT-UNX mice developed compensatory renal hypertrophy as expected, whereas K0-UNX mice did not. K0-UNX mice exhibited higher blood pressure, reduced glomerular filtration rate, and significant increase in proteinuria and glomerulosclerosis compared to WT-UNX. Expression of endothelial nitric oxide synthase (official name Nos3), a known transcriptional target gene of KLF2, was significantly reduced and dysregulation of other endothelial genes was also observed in the glomeruli of K0-UNX when compared to WT-UNX and sham-operated mice. Furthermore, both podocyte number and expression of podocyte markers were also significantly reduced in K0-UNX glomeruli, indicating a potential cross talk between glomerular endothelial cells and podocytes. Finally, decreased renal expression of KLF2 in nephrectomy patients was associated with the progression of kidney disease. Taken together, our data demonstrate a protective role of KLF2 against glomerular endothelial cell injury and progression of chronic kidney disease in the model of compensatory renal hypertrophy.
引用
收藏
页码:2021 / 2031
页数:11
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