Reduced Krüppel-Like Factor 2 Aggravates Glomerular Endothelial Cell Injury and Kidney Disease in Mice with Unilateral Nephrectomy.
Loss of functional nephrons induces compensatory glomerular hyperfiltration and hypertrophy, leading to the progression of chronic kidney disease. Krüppel-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 KO-UNX mice did not. KO-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 KO-UNX when compared to WT-UNX and sham-operated mice. Furthermore, both podocyte number and expression of podocyte markers were also significantly reduced in KO-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.
Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Nephrology, Hang Zhou Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou, China.
Fang
F
Zhong
Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York.
Sandeep K
SK
Mallipattu
Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York.
Chelsea
C
Estrada
Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York.
Madhav
M
Menon
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York.
Fadi
F
Salem
Department of Medicine, Case Cardiovascular Institute Research Institute, Case Western Reserve University, Cleveland, Ohio.
Mukesh K
MK
Jain
Department of Nephrology, Hang Zhou Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou, China.
Hongyu
H
Chen
Department of Nephrology, Hang Zhou Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou, China.
Yongjun
Y
Wang
Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York.
Kyung
K
Lee
Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York; Renal Section, James J. Peters Veterans Affairs Medical Center, Bronx, New York. Electronic address: cijiang.he@mssm.edu.
John C
JC
He
D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000473:pathology; D005455:Fluorescent Antibody Technique; D005919:Glomerular Filtration Rate; D006984:Hypertrophy; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000473:pathology*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009392:Nephrectomy; D060888:Real-Time Polymerase Chain Reaction; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000473:pathology*
C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors