title: Deletion of Lkb1 in Renal Tubular Epithelial Cells Leads to CKD by Altering Metabolism.
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.
authors.affiliation: Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea;
authors.forename: Seung Hyeok
authors.initials: SH
authors.lastname: Han
authors.affiliation: Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania;
authors.forename: Laura
authors.initials: L
authors.lastname: Malaga-Dieguez
authors.affiliation: Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania;
authors.forename: Frank
authors.initials: F
authors.lastname: Chinga
authors.affiliation: Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania;
authors.forename: Hyun Mi
authors.initials: HM
authors.lastname: Kang
authors.affiliation: Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Division of Nephrology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Jianling
authors.initials: J
authors.lastname: Tao
authors.affiliation: Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York; and.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Reidy
authors.affiliation: Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; ksusztak@mail.med.upenn.edu.
authors.forename: Katalin
authors.initials: K
authors.lastname: Susztak
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D004847:Epithelial Cells / Q000378:metabolism*; D017353:Gene Deletion; D007684:Kidney Tubules / Q000166:cytology; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D051436:Renal Insufficiency, Chronic / Q000235:genetics* / Q000378:metabolism*; D019459:Urothelium / Q000166:cytology
chemical_list: D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases
keywords: apoptosis; metabolism; renal cell biology; renal fibrosis