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 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. 27: 439-453, 201627: 439-453, . doi: 10.1681 Renal tubular epithelial cells (TECs) display strict apico-basal polarity. They allow a highly regulated uptake or excretion of substances at its apical surface, while keeping a closed, impenetrable surface through the formation of tight intercellular junctions in the basolateral membrane. The establishment and maintenance of TEC polarity is incompletely understood. The liver kinase B1 (LKB1) is an important regular of polarity. Early studies indicated that single intestinal epithelial cells polarize in a cell-autonomous fashion in response to LKB1 expression. 1 The LKB1 or STK11 gene encodes an evolutionarily conserved serine/threonine protein kinase. Following LKB1 expression, intestinal epithelial cells reorganized their cytoskeleton to form an apical brush border, demonstrating LKB1's critical role in establishing epithelial polarity. On the other hand, the effect of LKB1 on cell polarity appears to be cell type specific and deletion of LKB1 did not alter polarity of lung epithelial and pancreatic cells. 2 J Am Soc Nephrol

Metabolic reprogramming and tolerance during sepsis-induced AKI

“…An inability to switch metabolism from aerobic glycolysis to OXPHOS, and thus ‘turn off’ inflammation, has been associated with chronic inflammation and impaired organ recovery 62 . In inflammatory cells, the switch from this early anabolic glycolytic phase to an adaptive catabolic phase in which metabolism is reprogrammed towards OXPHOS and regulated to conserve energy, has been attributed to the action of Sirt1 and Sirt6 (REF.…”

“…3). Mice that were deficient in upstream regulators of NAD + /NADPH or were exposed to FAO inhibitors had substantial energy deficiencies, increased apoptosis and profibrotic phenotypes, all of which could be reversed by treatment with upstream activators of PGC-1α such as fenofibrate 62 .…”

“…Moreover, restoring FAO by activating key regulators such as PPAR-α and PGC-1α protected mice from tubulointerstitial fibrosis after exposure to folic acid. Mice that lacked LKB1, an upstream regulator of AMPK, also progressed to a fibrotic phenotype 62 , which was rescued and FAO restored using fenofibrate 74 . Activation of AMPK with A769662 resulted in the same effects, again suggesting that different mediators of this energy regulatory pathway have key roles in regulating progression to the mechanisms that lead to CKD.…”

Increasing the level of peroxisome proliferator-activated receptor γ coactivator-1α in podocytes results in collapsing glomerulopathy

“…These observations only support the potential benefit of improving bioenergetics, but not directly PGC1α. There are several other transcription factors in the kidney those expression is also reduced in glomerulosclerosis and might have overlapping functions with PGC1α (30)(31)(32)(33)(34). For this reason, here we performed studies to directly address the role of PGC1α in podocytes.…”

Arginine Vasopressin Promotes Redistribution of Adhesion Junction Protein E-Cadherin in Kidney Epithelial Cells

“…This newly observed evidence strongly suggests the correlation between cell polarity and CKD. 10 Besides the above-mentioned pathological observations, large-scale retrospective studies suggested a high-level plasma copeptin (a surrogate of vasopressin), is associated with the progression of kidney diseases. [11][12][13][14][15] For example, positive associations were found between copeptin levels with disease severity in autosomal dominant polycystic kidney disease (ADPKD) patients.…”