Cargando…
Angiotensin II Stimulation of DPP4 Activity Regulates Megalin in the Proximal Tubules
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 thou...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881597/ https://www.ncbi.nlm.nih.gov/pubmed/27213360 http://dx.doi.org/10.3390/ijms17050780 |
_version_ | 1782433994085761024 |
---|---|
author | Aroor, Annayya Zuberek, Marcin Duta, Cornel Meuth, Alex Sowers, James R. Whaley-Connell, Adam Nistala, Ravi |
author_facet | Aroor, Annayya Zuberek, Marcin Duta, Cornel Meuth, Alex Sowers, James R. Whaley-Connell, Adam Nistala, Ravi |
author_sort | Aroor, Annayya |
collection | PubMed |
description | 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 (AT(1)R) 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-AT(1)R 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 AT(1)R 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. |
format | Online Article Text |
id | pubmed-4881597 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-48815972016-05-27 Angiotensin II Stimulation of DPP4 Activity Regulates Megalin in the Proximal Tubules Aroor, Annayya Zuberek, Marcin Duta, Cornel Meuth, Alex Sowers, James R. Whaley-Connell, Adam Nistala, Ravi Int J Mol Sci Article 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 (AT(1)R) 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-AT(1)R 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 AT(1)R 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. MDPI 2016-05-20 /pmc/articles/PMC4881597/ /pubmed/27213360 http://dx.doi.org/10.3390/ijms17050780 Text en © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Aroor, Annayya Zuberek, Marcin Duta, Cornel Meuth, Alex Sowers, James R. Whaley-Connell, Adam Nistala, Ravi Angiotensin II Stimulation of DPP4 Activity Regulates Megalin in the Proximal Tubules |
title | Angiotensin II Stimulation of DPP4 Activity Regulates Megalin in the Proximal Tubules |
title_full | Angiotensin II Stimulation of DPP4 Activity Regulates Megalin in the Proximal Tubules |
title_fullStr | Angiotensin II Stimulation of DPP4 Activity Regulates Megalin in the Proximal Tubules |
title_full_unstemmed | Angiotensin II Stimulation of DPP4 Activity Regulates Megalin in the Proximal Tubules |
title_short | Angiotensin II Stimulation of DPP4 Activity Regulates Megalin in the Proximal Tubules |
title_sort | angiotensin ii stimulation of dpp4 activity regulates megalin in the proximal tubules |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881597/ https://www.ncbi.nlm.nih.gov/pubmed/27213360 http://dx.doi.org/10.3390/ijms17050780 |
work_keys_str_mv | AT aroorannayya angiotensiniistimulationofdpp4activityregulatesmegalinintheproximaltubules AT zuberekmarcin angiotensiniistimulationofdpp4activityregulatesmegalinintheproximaltubules AT dutacornel angiotensiniistimulationofdpp4activityregulatesmegalinintheproximaltubules AT meuthalex angiotensiniistimulationofdpp4activityregulatesmegalinintheproximaltubules AT sowersjamesr angiotensiniistimulationofdpp4activityregulatesmegalinintheproximaltubules AT whaleyconnelladam angiotensiniistimulationofdpp4activityregulatesmegalinintheproximaltubules AT nistalaravi angiotensiniistimulationofdpp4activityregulatesmegalinintheproximaltubules |