Cargando…
Activation of the Renin–Angiotensin System Disrupts the Cytoskeletal Architecture of Human Urine-Derived Podocytes
High blood pressure is one of the major public health problems that causes severe disorders in several tissues including the human kidney. One of the most important signaling pathways associated with the regulation of blood pressure is the renin–angiotensin system (RAS), with its main mediator angio...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8997628/ https://www.ncbi.nlm.nih.gov/pubmed/35406662 http://dx.doi.org/10.3390/cells11071095 |
_version_ | 1784684751739682816 |
---|---|
author | Erichsen, Lars Thimm, Chantelle Bohndorf, Martina Rahman, Md Shaifur Wruck, Wasco Adjaye, James |
author_facet | Erichsen, Lars Thimm, Chantelle Bohndorf, Martina Rahman, Md Shaifur Wruck, Wasco Adjaye, James |
author_sort | Erichsen, Lars |
collection | PubMed |
description | High blood pressure is one of the major public health problems that causes severe disorders in several tissues including the human kidney. One of the most important signaling pathways associated with the regulation of blood pressure is the renin–angiotensin system (RAS), with its main mediator angiotensin II (ANGII). Elevated levels of circulating and intracellular ANGII and aldosterone lead to pro-fibrotic, -inflammatory, and -hypertrophic milieu that causes remodeling and dysfunction in cardiovascular and renal tissues. Furthermore, ANGII has been recognized as a major risk factor for the induction of apoptosis in podocytes, ultimately leading to chronic kidney disease (CKD). In the past, disease modeling of kidney-associated diseases was extremely difficult, as the derivation of kidney originated cells is very challenging. Here we describe a differentiation protocol for reproducible differentiation of sine oculis homeobox homolog 2 (SIX2)-positive urine-derived renal progenitor cells (UdRPCs) into podocytes bearing typical cellular processes. The UdRPCs-derived podocytes show the activation of the renin–angiotensin system by being responsive to ANGII stimulation. Our data reveal the ANGII-dependent downregulation of nephrin (NPHS1) and synaptopodin (SYNPO), resulting in the disruption of the podocyte cytoskeletal architecture, as shown by immunofluorescence-based detection of α-Actinin. Furthermore, we show that the cytoskeletal disruption is mainly mediated through angiotensin II receptor type 1 (AGTR1) signaling and can be rescued by AGTR1 inhibition with the selective, competitive angiotensin II receptor type 1 antagonist, losartan. In the present manuscript we confirm and propose UdRPCs differentiated to podocytes as a unique cell type useful for studying nephrogenesis and associated diseases. Furthermore, the responsiveness of UdRPCs-derived podocytes to ANGII implies potential applications in nephrotoxicity studies and drug screening. |
format | Online Article Text |
id | pubmed-8997628 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-89976282022-04-12 Activation of the Renin–Angiotensin System Disrupts the Cytoskeletal Architecture of Human Urine-Derived Podocytes Erichsen, Lars Thimm, Chantelle Bohndorf, Martina Rahman, Md Shaifur Wruck, Wasco Adjaye, James Cells Article High blood pressure is one of the major public health problems that causes severe disorders in several tissues including the human kidney. One of the most important signaling pathways associated with the regulation of blood pressure is the renin–angiotensin system (RAS), with its main mediator angiotensin II (ANGII). Elevated levels of circulating and intracellular ANGII and aldosterone lead to pro-fibrotic, -inflammatory, and -hypertrophic milieu that causes remodeling and dysfunction in cardiovascular and renal tissues. Furthermore, ANGII has been recognized as a major risk factor for the induction of apoptosis in podocytes, ultimately leading to chronic kidney disease (CKD). In the past, disease modeling of kidney-associated diseases was extremely difficult, as the derivation of kidney originated cells is very challenging. Here we describe a differentiation protocol for reproducible differentiation of sine oculis homeobox homolog 2 (SIX2)-positive urine-derived renal progenitor cells (UdRPCs) into podocytes bearing typical cellular processes. The UdRPCs-derived podocytes show the activation of the renin–angiotensin system by being responsive to ANGII stimulation. Our data reveal the ANGII-dependent downregulation of nephrin (NPHS1) and synaptopodin (SYNPO), resulting in the disruption of the podocyte cytoskeletal architecture, as shown by immunofluorescence-based detection of α-Actinin. Furthermore, we show that the cytoskeletal disruption is mainly mediated through angiotensin II receptor type 1 (AGTR1) signaling and can be rescued by AGTR1 inhibition with the selective, competitive angiotensin II receptor type 1 antagonist, losartan. In the present manuscript we confirm and propose UdRPCs differentiated to podocytes as a unique cell type useful for studying nephrogenesis and associated diseases. Furthermore, the responsiveness of UdRPCs-derived podocytes to ANGII implies potential applications in nephrotoxicity studies and drug screening. MDPI 2022-03-24 /pmc/articles/PMC8997628/ /pubmed/35406662 http://dx.doi.org/10.3390/cells11071095 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Erichsen, Lars Thimm, Chantelle Bohndorf, Martina Rahman, Md Shaifur Wruck, Wasco Adjaye, James Activation of the Renin–Angiotensin System Disrupts the Cytoskeletal Architecture of Human Urine-Derived Podocytes |
title | Activation of the Renin–Angiotensin System Disrupts the Cytoskeletal Architecture of Human Urine-Derived Podocytes |
title_full | Activation of the Renin–Angiotensin System Disrupts the Cytoskeletal Architecture of Human Urine-Derived Podocytes |
title_fullStr | Activation of the Renin–Angiotensin System Disrupts the Cytoskeletal Architecture of Human Urine-Derived Podocytes |
title_full_unstemmed | Activation of the Renin–Angiotensin System Disrupts the Cytoskeletal Architecture of Human Urine-Derived Podocytes |
title_short | Activation of the Renin–Angiotensin System Disrupts the Cytoskeletal Architecture of Human Urine-Derived Podocytes |
title_sort | activation of the renin–angiotensin system disrupts the cytoskeletal architecture of human urine-derived podocytes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8997628/ https://www.ncbi.nlm.nih.gov/pubmed/35406662 http://dx.doi.org/10.3390/cells11071095 |
work_keys_str_mv | AT erichsenlars activationofthereninangiotensinsystemdisruptsthecytoskeletalarchitectureofhumanurinederivedpodocytes AT thimmchantelle activationofthereninangiotensinsystemdisruptsthecytoskeletalarchitectureofhumanurinederivedpodocytes AT bohndorfmartina activationofthereninangiotensinsystemdisruptsthecytoskeletalarchitectureofhumanurinederivedpodocytes AT rahmanmdshaifur activationofthereninangiotensinsystemdisruptsthecytoskeletalarchitectureofhumanurinederivedpodocytes AT wruckwasco activationofthereninangiotensinsystemdisruptsthecytoskeletalarchitectureofhumanurinederivedpodocytes AT adjayejames activationofthereninangiotensinsystemdisruptsthecytoskeletalarchitectureofhumanurinederivedpodocytes |