title: Angiotensin II Stimulation of DPP4 Activity Regulates Megalin in the Proximal Tubules.
abstract: Proteinuria is a marker of incipient kidney injury in many disorders, including obesity. Previously, we demonstrated that megalin, a receptor endocytotic protein in the proximal tubule, is downregulated in obese mice, which was prevented by inhibition of dipeptidyl protease 4 (DPP4). Obesity is thought to be associated with upregulation of intra-renal angiotensin II (Ang II) signaling via the Ang II Type 1 receptor (AT₁R) and Ang II suppresses megalin expression in proximal tubule cells in vitro. Therefore, we tested the hypothesis that Ang II will suppress megalin protein via activation of DPP4. We used Ang II (200 ng/kg/min) infusion in mice and Ang II (10(-8) M) treatment of T35OK-AT₁R proximal tubule cells to test our hypothesis. Ang II-infused mouse kidneys displayed increases in DPP4 activity and decreases in megalin. In proximal tubule cells, Ang II stimulated DPP4 activity concurrent with suppression of megalin. MK0626, a DPP4 inhibitor, partially restored megalin expression similar to U0126, a mitogen activated protein kinase (MAPK)/extracellular regulated kinase (ERK) kinase kinase (MEK) 1/2 inhibitor and AG1478, an epidermal growth factor receptor (EGFR) inhibitor. Similarly, Ang II-induced ERK phosphorylation was suppressed with MK0626 and Ang II-induced DPP4 activity was suppressed by U0126. Therefore, our study reveals a cross talk between AT₁R signaling and DPP4 activation in the regulation of megalin and underscores the significance of targeting DPP4 in the prevention of obesity related kidney injury progression.
authors.affiliation: Divisions of Endocrinology and Nephrology, Department of Medicine, University of Missouri-Columbia, Columbia, MO 65212, USA. aroora@health.missouri.edu.|School of Medicine, University of Missouri-Columbia, Columbia, MO 65212, USA. aroora@health.missouri.edu.|Harry S. Truman Memorial Veteran's Hospital, Columbia, MO 65201, USA. aroora@health.missouri.edu.
authors.forename: Annayya
authors.initials: A
authors.lastname: Aroor
authors.affiliation: School of Medicine, University of Missouri-Columbia, Columbia, MO 65212, USA. mjzg28@health.missouri.edu.
authors.forename: Marcin
authors.initials: M
authors.lastname: Zuberek
authors.affiliation: Divisions of Endocrinology and Nephrology, Department of Medicine, University of Missouri-Columbia, Columbia, MO 65212, USA. cduta@fayettenews.com.
authors.forename: Cornel
authors.initials: C
authors.lastname: Duta
authors.affiliation: Divisions of Endocrinology and Nephrology, Department of Medicine, University of Missouri-Columbia, Columbia, MO 65212, USA. meutha@health.missouri.edu.|School of Medicine, University of Missouri-Columbia, Columbia, MO 65212, USA. meutha@health.missouri.edu.|Harry S. Truman Memorial Veteran's Hospital, Columbia, MO 65201, USA. meutha@health.missouri.edu.
authors.forename: Alex
authors.initials: A
authors.lastname: Meuth
authors.affiliation: Divisions of Endocrinology and Nephrology, Department of Medicine, University of Missouri-Columbia, Columbia, MO 65212, USA. sowersj@health.missouri.edu.|School of Medicine, University of Missouri-Columbia, Columbia, MO 65212, USA. sowersj@health.missouri.edu.|Harry S. Truman Memorial Veteran's Hospital, Columbia, MO 65201, USA. sowersj@health.missouri.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
authors.affiliation: Divisions of Endocrinology and Nephrology, Department of Medicine, University of Missouri-Columbia, Columbia, MO 65212, USA. whaleyconnella@health.missouri.edu.|School of Medicine, University of Missouri-Columbia, Columbia, MO 65212, USA. whaleyconnella@health.missouri.edu.|Harry S. Truman Memorial Veteran's Hospital, Columbia, MO 65201, USA. whaleyconnella@health.missouri.edu.
authors.forename: Adam
authors.initials: A
authors.lastname: Whaley-Connell
authors.affiliation: Divisions of Endocrinology and Nephrology, Department of Medicine, University of Missouri-Columbia, Columbia, MO 65212, USA. nistalar@health.missouri.edu.|School of Medicine, University of Missouri-Columbia, Columbia, MO 65212, USA. nistalar@health.missouri.edu.|Harry S. Truman Memorial Veteran's Hospital, Columbia, MO 65201, USA. nistalar@health.missouri.edu.
authors.forename: Ravi
authors.initials: R
authors.lastname: Nistala
mesh_terms: D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000096:biosynthesis*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000150:complications / Q000378:metabolism; D051437:Renal Insufficiency / Q000209:etiology / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D026561:Low Density Lipoprotein Receptor-Related Protein-2; C055127:Lrp2 protein, mouse; D000804:Angiotensin II; D048049:Extracellular Signal-Regulated MAP Kinases; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse
keywords: AT1R; DPP4; EGFR; ERK; megalin; obesity related kidney disease; proteinuria