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Deletion of Lkb1 in Renal Tubular Epithelial Cells Leads to CKD by Altering Metabolism

Authors
 Seung Hyeok Han  ;  Laura Malaga-Dieguez  ;  Frank Chinga  ;  Hyun Mi Kang  ;  Jianling Tao  ;  Kimberly Reidy  ;  Katalin Susztak 
Citation
 JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol.27(2) : 439-453, 2016 
Journal Title
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
ISSN
 1046-6673 
Issue Date
2016
MeSH
Animals ; Epithelial Cells/metabolism* ; Gene Deletion* ; Kidney Tubules/cytology ; Mice ; Protein-Serine-Threonine Kinases/genetics* ; Renal Insufficiency, Chronic/genetics* ; Renal Insufficiency, Chronic/metabolism* ; Urothelium/cytology
Keywords
apoptosis ; metabolism ; renal cell biology ; renal fibrosis
Abstract
Renal tubule epithelial cells are high-energy demanding polarized epithelial cells. Liver kinase B1 (LKB1) is a key regulator of polarity, proliferation, and cell metabolism in epithelial cells, but the function of LKB1 in the kidney is unclear. Our unbiased gene expression studies of human control and CKD kidney samples identified lower expression of LKB1 and regulatory proteins in CKD. Mice with distal tubule epithelial-specific Lkb1 deletion (Ksp-Cre/Lkb1(flox/flox)) exhibited progressive kidney disease characterized by flattened dedifferentiated tubule epithelial cells, interstitial matrix accumulation, and dilated cystic-appearing tubules. Expression of epithelial polarity markers β-catenin and E-cadherin was not altered even at later stages. However, expression levels of key regulators of metabolism, AMP-activated protein kinase (Ampk), peroxisome proliferative activated receptor gamma coactivator 1-α (Ppargc1a), and Ppara, were significantly lower than those in controls and correlated with fibrosis development. Loss of Lkb1 in cultured epithelial cells resulted in energy depletion, apoptosis, less fatty acid oxidation and glycolysis, and a profibrotic phenotype. Treatment of Lkb1-deficient cells with an AMP-activated protein kinase (AMPK) agonist (A769662) or a peroxisome proliferative activated receptor alpha agonist (fenofibrate) restored the fatty oxidation defect and reduced apoptosis. In conclusion, we show that loss of LKB1 in renal tubular epithelial cells has an important role in kidney disease development by influencing intracellular metabolism.
Full Text
http://jasn.asnjournals.org/content/27/2/439
DOI
10.1681/ASN.2014121181
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Han, Seung Hyeok(한승혁) ORCID logo https://orcid.org/0000-0001-7923-5635
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/146358
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