title: Acute leptin exposure reduces megalin expression and upregulates TGFβ1 in cultured renal proximal tubule cells.
abstract: Increased leptin concentrations observed in obesity can lead to proteinuria, suggesting that leptin may play a role in obesity-related kidney disease. Obesity reduces activation of AMP-activated protein kinase (AMPK) and increases transforming growth factor-β1 (TGF-β1) expression in the kidney, leading to albuminuria. Thus we investigated if elevated leptin altered AMPK and TGF-β1 signaling in proximal tubule cells (PTCs). In opossum kidney (OK) PTCs Western blot analysis demonstrated that leptin upregulates TGF-β1 secretion (0.50 µg/ml) and phosphorylated AMPKα (at 0.25, and 0.50 µg/ml), and downregulates megalin expression at all concentrations (0.05-0.50 µg/ml). Using the AMPK inhibitor, Compound C, leptin exposure regulated TGF-β1 expression and secretion in PTCs via an AMPK mediated pathway. In addition, elevated leptin exposure (0.50 µg/ml) reduced albumin handling in OK cells independently of megalin expression. This study demonstrates that leptin upregulates TGF-β1, reduces megalin, and reduces albumin handling in PTCs by an AMPK mediated pathway.
authors.affiliation: Centre for Chronic Disease Prevention and Management, College of Health and Biomedicine, Victoria University, St Albans, Vic. 3021, Australia; Department of Physiology, The University of Melbourne, Parkville, Vic. 3010, Australia.
authors.forename: Jessica F
authors.initials: JF
authors.lastname: Briffa
authors.affiliation: Centre for Chronic Disease Prevention and Management, College of Health and Biomedicine, Victoria University, St Albans, Vic. 3021, Australia.
authors.forename: Esther
authors.initials: E
authors.lastname: Grinfeld
authors.affiliation: Centre for Chronic Disease Prevention and Management, College of Health and Biomedicine, Victoria University, St Albans, Vic. 3021, Australia.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Mathai
authors.affiliation: School of Medical Sciences, The Bosch Institute, The University of Sydney, NSW 2006, Australia.
authors.forename: Phillip
authors.initials: P
authors.lastname: Poronnik
authors.affiliation: Centre for Chronic Disease Prevention and Management, College of Health and Biomedicine, Victoria University, St Albans, Vic. 3021, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McAinch
authors.affiliation: Centre for Chronic Disease Prevention and Management, College of Health and Biomedicine, Victoria University, St Albans, Vic. 3021, Australia; Department of Physiology, The University of Melbourne, Parkville, Vic. 3010, Australia. Electronic address: deanne.skelly@unimelb.edu.au.
authors.forename: Deanne H
authors.initials: DH
authors.lastname: Hryciw
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000502:physiology*; D020738:Leptin / Q000378:metabolism*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism*; D008297:Male; D009893:Opossums; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D020738:Leptin; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Leptin; Megalin; Proximal tubule; TGF-β1