Cargando…

Oxidative Stress and Mitochondrial Abnormalities Contribute to Decreased Endothelial Nitric Oxide Synthase Expression and Renal Disease Progression in Early Experimental Polycystic Kidney Disease

Vascular abnormalities are the most important non-cystic complications in Polycystic Kidney Disease (PKD) and contribute to renal disease progression. Endothelial dysfunction and oxidative stress are evident in patients with ADPKD, preserved renal function, and controlled hypertension. The underlyin...

Descripción completa

Detalles Bibliográficos
Autores principales: Kahveci, Alp S., Barnatan, Tania T., Kahveci, Ali, Adrian, Alexis E., Arroyo, Jennifer, Eirin, Alfonso, Harris, Peter C., Lerman, Amir, Lerman, Lilach O., Torres, Vicente E., Irazabal, Maria V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139316/
https://www.ncbi.nlm.nih.gov/pubmed/32183375
http://dx.doi.org/10.3390/ijms21061994
_version_ 1783518737704419328
author Kahveci, Alp S.
Barnatan, Tania T.
Kahveci, Ali
Adrian, Alexis E.
Arroyo, Jennifer
Eirin, Alfonso
Harris, Peter C.
Lerman, Amir
Lerman, Lilach O.
Torres, Vicente E.
Irazabal, Maria V.
author_facet Kahveci, Alp S.
Barnatan, Tania T.
Kahveci, Ali
Adrian, Alexis E.
Arroyo, Jennifer
Eirin, Alfonso
Harris, Peter C.
Lerman, Amir
Lerman, Lilach O.
Torres, Vicente E.
Irazabal, Maria V.
author_sort Kahveci, Alp S.
collection PubMed
description Vascular abnormalities are the most important non-cystic complications in Polycystic Kidney Disease (PKD) and contribute to renal disease progression. Endothelial dysfunction and oxidative stress are evident in patients with ADPKD, preserved renal function, and controlled hypertension. The underlying biological mechanisms remain unknown. We hypothesized that in early ADPKD, the reactive oxygen species (ROS)-producing nicotinamide adenine dinucleotide phosphate hydrogen (NAD(P)H)-oxidase complex-4 (NOX4), a major source of ROS in renal tubular epithelial cells (TECs) and endothelial cells (ECs), induces EC mitochondrial abnormalities, contributing to endothelial dysfunction, vascular abnormalities, and renal disease progression. Renal oxidative stress, mitochondrial morphology (electron microscopy), and NOX4 expression were assessed in 4- and 12-week-old PCK and Sprague-Dawley (wild-type, WT) control rats (n = 8 males and 8 females each). Endothelial function was assessed by renal expression of endothelial nitric oxide synthase (eNOS). Peritubular capillaries were counted in hematoxylin–eosin (H&E)-stained slides and correlated with the cystic index. The enlarged cystic kidneys of PCK rats exhibited significant accumulation of 8-hydroxyguanosine (8-OHdG) as early as 4 weeks of age, which became more pronounced at 12 weeks. Mitochondria of TECs lining cysts and ECs exhibited loss of cristae but remained preserved in non-cystic TECs. Renal expression of NOX4 was upregulated in TECs and ECs of PCK rats at 4 weeks of age and further increased at 12 weeks. Contrarily, eNOS immunoreactivity was lower in PCK vs. WT rats at 4 weeks and further decreased at 12 weeks. The peritubular capillary index was lower in PCK vs. WT rats at 12 weeks and correlated inversely with the cystic index. Early PKD is associated with NOX4-induced oxidative stress and mitochondrial abnormalities predominantly in ECs and TECs lining cysts. Endothelial dysfunction precedes capillary loss, and the latter correlates with worsening of renal disease. These observations position NOX4 and EC mitochondria as potential therapeutic targets in PKD.
format Online
Article
Text
id pubmed-7139316
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-71393162020-04-10 Oxidative Stress and Mitochondrial Abnormalities Contribute to Decreased Endothelial Nitric Oxide Synthase Expression and Renal Disease Progression in Early Experimental Polycystic Kidney Disease Kahveci, Alp S. Barnatan, Tania T. Kahveci, Ali Adrian, Alexis E. Arroyo, Jennifer Eirin, Alfonso Harris, Peter C. Lerman, Amir Lerman, Lilach O. Torres, Vicente E. Irazabal, Maria V. Int J Mol Sci Article Vascular abnormalities are the most important non-cystic complications in Polycystic Kidney Disease (PKD) and contribute to renal disease progression. Endothelial dysfunction and oxidative stress are evident in patients with ADPKD, preserved renal function, and controlled hypertension. The underlying biological mechanisms remain unknown. We hypothesized that in early ADPKD, the reactive oxygen species (ROS)-producing nicotinamide adenine dinucleotide phosphate hydrogen (NAD(P)H)-oxidase complex-4 (NOX4), a major source of ROS in renal tubular epithelial cells (TECs) and endothelial cells (ECs), induces EC mitochondrial abnormalities, contributing to endothelial dysfunction, vascular abnormalities, and renal disease progression. Renal oxidative stress, mitochondrial morphology (electron microscopy), and NOX4 expression were assessed in 4- and 12-week-old PCK and Sprague-Dawley (wild-type, WT) control rats (n = 8 males and 8 females each). Endothelial function was assessed by renal expression of endothelial nitric oxide synthase (eNOS). Peritubular capillaries were counted in hematoxylin–eosin (H&E)-stained slides and correlated with the cystic index. The enlarged cystic kidneys of PCK rats exhibited significant accumulation of 8-hydroxyguanosine (8-OHdG) as early as 4 weeks of age, which became more pronounced at 12 weeks. Mitochondria of TECs lining cysts and ECs exhibited loss of cristae but remained preserved in non-cystic TECs. Renal expression of NOX4 was upregulated in TECs and ECs of PCK rats at 4 weeks of age and further increased at 12 weeks. Contrarily, eNOS immunoreactivity was lower in PCK vs. WT rats at 4 weeks and further decreased at 12 weeks. The peritubular capillary index was lower in PCK vs. WT rats at 12 weeks and correlated inversely with the cystic index. Early PKD is associated with NOX4-induced oxidative stress and mitochondrial abnormalities predominantly in ECs and TECs lining cysts. Endothelial dysfunction precedes capillary loss, and the latter correlates with worsening of renal disease. These observations position NOX4 and EC mitochondria as potential therapeutic targets in PKD. MDPI 2020-03-14 /pmc/articles/PMC7139316/ /pubmed/32183375 http://dx.doi.org/10.3390/ijms21061994 Text en © 2020 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
Kahveci, Alp S.
Barnatan, Tania T.
Kahveci, Ali
Adrian, Alexis E.
Arroyo, Jennifer
Eirin, Alfonso
Harris, Peter C.
Lerman, Amir
Lerman, Lilach O.
Torres, Vicente E.
Irazabal, Maria V.
Oxidative Stress and Mitochondrial Abnormalities Contribute to Decreased Endothelial Nitric Oxide Synthase Expression and Renal Disease Progression in Early Experimental Polycystic Kidney Disease
title Oxidative Stress and Mitochondrial Abnormalities Contribute to Decreased Endothelial Nitric Oxide Synthase Expression and Renal Disease Progression in Early Experimental Polycystic Kidney Disease
title_full Oxidative Stress and Mitochondrial Abnormalities Contribute to Decreased Endothelial Nitric Oxide Synthase Expression and Renal Disease Progression in Early Experimental Polycystic Kidney Disease
title_fullStr Oxidative Stress and Mitochondrial Abnormalities Contribute to Decreased Endothelial Nitric Oxide Synthase Expression and Renal Disease Progression in Early Experimental Polycystic Kidney Disease
title_full_unstemmed Oxidative Stress and Mitochondrial Abnormalities Contribute to Decreased Endothelial Nitric Oxide Synthase Expression and Renal Disease Progression in Early Experimental Polycystic Kidney Disease
title_short Oxidative Stress and Mitochondrial Abnormalities Contribute to Decreased Endothelial Nitric Oxide Synthase Expression and Renal Disease Progression in Early Experimental Polycystic Kidney Disease
title_sort oxidative stress and mitochondrial abnormalities contribute to decreased endothelial nitric oxide synthase expression and renal disease progression in early experimental polycystic kidney disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139316/
https://www.ncbi.nlm.nih.gov/pubmed/32183375
http://dx.doi.org/10.3390/ijms21061994
work_keys_str_mv AT kahvecialps oxidativestressandmitochondrialabnormalitiescontributetodecreasedendothelialnitricoxidesynthaseexpressionandrenaldiseaseprogressioninearlyexperimentalpolycystickidneydisease
AT barnatantaniat oxidativestressandmitochondrialabnormalitiescontributetodecreasedendothelialnitricoxidesynthaseexpressionandrenaldiseaseprogressioninearlyexperimentalpolycystickidneydisease
AT kahveciali oxidativestressandmitochondrialabnormalitiescontributetodecreasedendothelialnitricoxidesynthaseexpressionandrenaldiseaseprogressioninearlyexperimentalpolycystickidneydisease
AT adrianalexise oxidativestressandmitochondrialabnormalitiescontributetodecreasedendothelialnitricoxidesynthaseexpressionandrenaldiseaseprogressioninearlyexperimentalpolycystickidneydisease
AT arroyojennifer oxidativestressandmitochondrialabnormalitiescontributetodecreasedendothelialnitricoxidesynthaseexpressionandrenaldiseaseprogressioninearlyexperimentalpolycystickidneydisease
AT eirinalfonso oxidativestressandmitochondrialabnormalitiescontributetodecreasedendothelialnitricoxidesynthaseexpressionandrenaldiseaseprogressioninearlyexperimentalpolycystickidneydisease
AT harrispeterc oxidativestressandmitochondrialabnormalitiescontributetodecreasedendothelialnitricoxidesynthaseexpressionandrenaldiseaseprogressioninearlyexperimentalpolycystickidneydisease
AT lermanamir oxidativestressandmitochondrialabnormalitiescontributetodecreasedendothelialnitricoxidesynthaseexpressionandrenaldiseaseprogressioninearlyexperimentalpolycystickidneydisease
AT lermanlilacho oxidativestressandmitochondrialabnormalitiescontributetodecreasedendothelialnitricoxidesynthaseexpressionandrenaldiseaseprogressioninearlyexperimentalpolycystickidneydisease
AT torresvicentee oxidativestressandmitochondrialabnormalitiescontributetodecreasedendothelialnitricoxidesynthaseexpressionandrenaldiseaseprogressioninearlyexperimentalpolycystickidneydisease
AT irazabalmariav oxidativestressandmitochondrialabnormalitiescontributetodecreasedendothelialnitricoxidesynthaseexpressionandrenaldiseaseprogressioninearlyexperimentalpolycystickidneydisease