Deletion of Lkb1 in renal tubular epithelial cells leads to CKD by altering metabolism

Seung Hyeok Han, Laura Malaga-DIeguez, Frank Chinga, Hyun Mi Kang, Jianling Tao, Kimberly Reidy, Katalin Susztak

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

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 CKDkidney samples identified lower expression of LKB1 and regulatory proteins in CKD. Mice with distal tubule epithelial-specific Lkb1 deletion (Ksp-Cre/Lkb1flox/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 b-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-a (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.

Original languageEnglish (US)
Pages (from-to)439-453
Number of pages15
JournalJournal of the American Society of Nephrology
Volume27
Issue number2
DOIs
StatePublished - Feb 2016

ASJC Scopus subject areas

  • Nephrology

Fingerprint Dive into the research topics of 'Deletion of Lkb1 in renal tubular epithelial cells leads to CKD by altering metabolism'. Together they form a unique fingerprint.

Cite this