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Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms.
Kidney Int. 2006 Jan; 69(1):105-13.KI

Abstract

Recent evidence suggesting a strong interplay between components of the renin-angiotensin system and key mediators of fibrosis led us to hypothesize that renin, independent of its enzymatic action to enhance angiotensin (Ang) II synthesis, directly increases production of the fibrogenic cytokine transforming growth factor (TGF)-beta. Human or rat mesangial cells (MCs) were treated with human recombinant renin (HrRenin) or rat recombinant renin (RrRenin) and the effects on TGF-beta1, plasminogen activator inhibitor-type 1 (PAI-1), fibronectin (FN) and collagen 1 mRNA and protein were investigated. Blockade of the rat MC renin receptor was achieved using siRNA. HrRenin or RrRenin, at doses shown to be physiologically relevant, induced marked dose- and time-dependent increases in TGF-beta1. These effects were not altered by adding an inhibitor of renin's enzymatic action (RO 42-5892), the Ang II receptor antagonist losartan or the Ang-converting enzyme inhibitor enalapril. RrRenin also induced PAI-1, FN and collagen 1 mRNA and PAI-1 and FN protein in a dose-dependent manner. Neutralizing antibodies to TGF-beta partially blocked these effects. Supernatant and cell lysate Ang I and Ang II levels were extremely low. MC angiotensinogen mRNA was undetectable both with and without added renin. Targeting of the rat renin receptor mRNA with siRNA blocked induction of TGF-beta1. We conclude that renin upregulates MC TGF-beta1 through a receptor-mediated mechanism, independent of Ang II generation or action. Renin-induced increases in TGF-beta1 in turn stimulate increases in PAI-1, FN and collagen I. Thus, renin may contribute to renal fibrotic disease, particularly when therapeutic Ang II blockade elevates plasma renin.

Authors+Show Affiliations

Fibrosis Research Laboratory, Division of Nephrology, Department of Medicine, University of Utah, Salt Lake City, Utah 84108, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16374430

Citation

Huang, Y, et al. "Renin Increases Mesangial Cell Transforming Growth Factor-beta1 and Matrix Proteins Through Receptor-mediated, Angiotensin II-independent Mechanisms." Kidney International, vol. 69, no. 1, 2006, pp. 105-13.
Huang Y, Wongamorntham S, Kasting J, et al. Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms. Kidney Int. 2006;69(1):105-13.
Huang, Y., Wongamorntham, S., Kasting, J., McQuillan, D., Owens, R. T., Yu, L., Noble, N. A., & Border, W. (2006). Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms. Kidney International, 69(1), 105-13.
Huang Y, et al. Renin Increases Mesangial Cell Transforming Growth Factor-beta1 and Matrix Proteins Through Receptor-mediated, Angiotensin II-independent Mechanisms. Kidney Int. 2006;69(1):105-13. PubMed PMID: 16374430.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms. AU - Huang,Y, AU - Wongamorntham,S, AU - Kasting,J, AU - McQuillan,D, AU - Owens,R T, AU - Yu,L, AU - Noble,N A, AU - Border,W, PY - 2005/12/24/pubmed PY - 2006/3/3/medline PY - 2005/12/24/entrez SP - 105 EP - 13 JF - Kidney international JO - Kidney Int. VL - 69 IS - 1 N2 - Recent evidence suggesting a strong interplay between components of the renin-angiotensin system and key mediators of fibrosis led us to hypothesize that renin, independent of its enzymatic action to enhance angiotensin (Ang) II synthesis, directly increases production of the fibrogenic cytokine transforming growth factor (TGF)-beta. Human or rat mesangial cells (MCs) were treated with human recombinant renin (HrRenin) or rat recombinant renin (RrRenin) and the effects on TGF-beta1, plasminogen activator inhibitor-type 1 (PAI-1), fibronectin (FN) and collagen 1 mRNA and protein were investigated. Blockade of the rat MC renin receptor was achieved using siRNA. HrRenin or RrRenin, at doses shown to be physiologically relevant, induced marked dose- and time-dependent increases in TGF-beta1. These effects were not altered by adding an inhibitor of renin's enzymatic action (RO 42-5892), the Ang II receptor antagonist losartan or the Ang-converting enzyme inhibitor enalapril. RrRenin also induced PAI-1, FN and collagen 1 mRNA and PAI-1 and FN protein in a dose-dependent manner. Neutralizing antibodies to TGF-beta partially blocked these effects. Supernatant and cell lysate Ang I and Ang II levels were extremely low. MC angiotensinogen mRNA was undetectable both with and without added renin. Targeting of the rat renin receptor mRNA with siRNA blocked induction of TGF-beta1. We conclude that renin upregulates MC TGF-beta1 through a receptor-mediated mechanism, independent of Ang II generation or action. Renin-induced increases in TGF-beta1 in turn stimulate increases in PAI-1, FN and collagen I. Thus, renin may contribute to renal fibrotic disease, particularly when therapeutic Ang II blockade elevates plasma renin. SN - 0085-2538 UR - https://www.unboundmedicine.com/medline/citation/16374430/Renin_increases_mesangial_cell_transforming_growth_factor_beta1_and_matrix_proteins_through_receptor_mediated_angiotensin_II_independent_mechanisms_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0085-2538(15)51309-4 DB - PRIME DP - Unbound Medicine ER -