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Prorenin independently causes hypertension and renal and cardiac fibrosis in cyp1a1-prorenin transgenic rats

Plasma prorenin is commonly elevated in diabetic patients and appears to predict the development of diabetic nephropathy. However, the pathological role of prorenin is unclear. In the present study, a transgenic, inducible, hepatic prorenin-overexpressing rat model was generated and the effect of pr...

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Autores principales: Zhou, Guangyu, Wu, Jie, Gu, Chunyan, Wang, Bin, Abel, E. Dale, Cheung, Alfred K., Huang, Yufeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6024026/
https://www.ncbi.nlm.nih.gov/pubmed/29848510
http://dx.doi.org/10.1042/CS20171659
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author Zhou, Guangyu
Wu, Jie
Gu, Chunyan
Wang, Bin
Abel, E. Dale
Cheung, Alfred K.
Huang, Yufeng
author_facet Zhou, Guangyu
Wu, Jie
Gu, Chunyan
Wang, Bin
Abel, E. Dale
Cheung, Alfred K.
Huang, Yufeng
author_sort Zhou, Guangyu
collection PubMed
description Plasma prorenin is commonly elevated in diabetic patients and appears to predict the development of diabetic nephropathy. However, the pathological role of prorenin is unclear. In the present study, a transgenic, inducible, hepatic prorenin-overexpressing rat model was generated and the effect of prorenin in organ injury was examined. Four groups of rats (cyp1a1 prorenin transgenic male and female rats and non-transgenic littermates) were assigned to receive a diet containing 0.3% of the transgene inducer indole-3-carbinol (I3C) for 4 weeks. Plasma prorenin concentration was increased and mean arterial pressure (MAP) increased from 80 ± 18 to 138 ± 17 (mmHg), whereas renal prorenin/renin protein expression was unchanged, in transgenic rats fed with I3C diet. The intact prorenin, not renin, in plasma and urine samples was further observed by Western blot analysis. Importantly, transgenic rats with high levels of prorenin developed albuminuria, glomerular and tubulointerstitial fibrosis associated with increased expression of transforming growth factor β (TGFβ) 1 (TGFβ1), plasminogen activator inhibitor-1 (PAI-1), collagen, and fibronectin (FN). These rats also exhibited cardiac hypertrophy determined by echocardiography, with elevated ratio of heart weight to body weight (HW/BW). Cardiac collagen in interstitial and perivascular regions was prominent, accompanied by the increase in mRNA contents of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), β-myosin heavy chain (β-MHC), TGFβ1, PAI-1, and collagen in the heart tissue. Furthermore, renal protein levels of p-NF-κB-p65 and monocyte chemoattractant protein-1 (MCP-1), NAPDH oxidases, malondialdehyde (MDA) and 8-isoprostane (8-IP), p-ERK, p-β-catenin, and p-Akt were dramatically increased in prorenin overexpressing rats. These results indicate that prorenin, without being converted into renin, causes hypertension, renal and cardiac fibrosis via the induction of inflammation, oxidative stress and the ERK, β-catenin, and Akt-mediated signals.
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spelling pubmed-60240262018-07-11 Prorenin independently causes hypertension and renal and cardiac fibrosis in cyp1a1-prorenin transgenic rats Zhou, Guangyu Wu, Jie Gu, Chunyan Wang, Bin Abel, E. Dale Cheung, Alfred K. Huang, Yufeng Clin Sci (Lond) Research Articles Plasma prorenin is commonly elevated in diabetic patients and appears to predict the development of diabetic nephropathy. However, the pathological role of prorenin is unclear. In the present study, a transgenic, inducible, hepatic prorenin-overexpressing rat model was generated and the effect of prorenin in organ injury was examined. Four groups of rats (cyp1a1 prorenin transgenic male and female rats and non-transgenic littermates) were assigned to receive a diet containing 0.3% of the transgene inducer indole-3-carbinol (I3C) for 4 weeks. Plasma prorenin concentration was increased and mean arterial pressure (MAP) increased from 80 ± 18 to 138 ± 17 (mmHg), whereas renal prorenin/renin protein expression was unchanged, in transgenic rats fed with I3C diet. The intact prorenin, not renin, in plasma and urine samples was further observed by Western blot analysis. Importantly, transgenic rats with high levels of prorenin developed albuminuria, glomerular and tubulointerstitial fibrosis associated with increased expression of transforming growth factor β (TGFβ) 1 (TGFβ1), plasminogen activator inhibitor-1 (PAI-1), collagen, and fibronectin (FN). These rats also exhibited cardiac hypertrophy determined by echocardiography, with elevated ratio of heart weight to body weight (HW/BW). Cardiac collagen in interstitial and perivascular regions was prominent, accompanied by the increase in mRNA contents of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), β-myosin heavy chain (β-MHC), TGFβ1, PAI-1, and collagen in the heart tissue. Furthermore, renal protein levels of p-NF-κB-p65 and monocyte chemoattractant protein-1 (MCP-1), NAPDH oxidases, malondialdehyde (MDA) and 8-isoprostane (8-IP), p-ERK, p-β-catenin, and p-Akt were dramatically increased in prorenin overexpressing rats. These results indicate that prorenin, without being converted into renin, causes hypertension, renal and cardiac fibrosis via the induction of inflammation, oxidative stress and the ERK, β-catenin, and Akt-mediated signals. Portland Press Ltd. 2018-06-28 /pmc/articles/PMC6024026/ /pubmed/29848510 http://dx.doi.org/10.1042/CS20171659 Text en © 2018 The Author(s). https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Research Articles
Zhou, Guangyu
Wu, Jie
Gu, Chunyan
Wang, Bin
Abel, E. Dale
Cheung, Alfred K.
Huang, Yufeng
Prorenin independently causes hypertension and renal and cardiac fibrosis in cyp1a1-prorenin transgenic rats
title Prorenin independently causes hypertension and renal and cardiac fibrosis in cyp1a1-prorenin transgenic rats
title_full Prorenin independently causes hypertension and renal and cardiac fibrosis in cyp1a1-prorenin transgenic rats
title_fullStr Prorenin independently causes hypertension and renal and cardiac fibrosis in cyp1a1-prorenin transgenic rats
title_full_unstemmed Prorenin independently causes hypertension and renal and cardiac fibrosis in cyp1a1-prorenin transgenic rats
title_short Prorenin independently causes hypertension and renal and cardiac fibrosis in cyp1a1-prorenin transgenic rats
title_sort prorenin independently causes hypertension and renal and cardiac fibrosis in cyp1a1-prorenin transgenic rats
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6024026/
https://www.ncbi.nlm.nih.gov/pubmed/29848510
http://dx.doi.org/10.1042/CS20171659
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