Folic Acid Mitigates Angiotensin-II-Induced Blood Pressure and Renal Remodeling

Clinical data suggests an association between systolic hypertension, renal function and hyperhomocysteinemia (HHcy). HHcy is a state of elevated plasma homocysteine (Hcy) levels and is known to cause vascular complications. In this study, we tested the hypothesis whether Ang II-induced hypertension...

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Vydané v:	PloS one Ročník 8; číslo 12; s. e83813
Hlavní autori:	Pushpakumar, Sathnur B., Kundu, Sourav, Metreveli, Naira, Sen, Utpal
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Public Library of Science 26.12.2013 Public Library of Science (PLoS)
Predmet:	Acids Angiogenesis Angiostatin Angiotensin Angiotensin II Angiotensin II - pharmacology Animals Arginine - analogs & derivatives Arginine - metabolism Biology Biophysics Blood Blood flow Blood pressure Blood Pressure - drug effects Cardiovascular disease Collagen (type IV) Collagen - metabolism Complications Drinking - drug effects Drinking water Drug dosages Endostatin Fibrosis Folic acid Folic Acid - pharmacology Gelatinase A Gene expression Gene Expression Regulation, Enzymologic - drug effects Homocysteine Homocysteine - blood Hyperhomocysteinemia Hyperhomocysteinemia - complications Hypertension Hypertension - chemically induced Hypertension - complications Hypertension - metabolism Hypertension - physiopathology Immunoglobulins Inflammation Kidney - physiopathology Laboratories Matrix Metalloproteinases - metabolism Medicine Mice Mice, Inbred C57BL Microvasculature mRNA Nitric Oxide - biosynthesis Nitric Oxide Synthase Type III - metabolism Oxidative stress Physiology Plasma Renal function RNA, Messenger - genetics RNA, Messenger - metabolism Rodents Tissue Inhibitor of Metalloproteinases - metabolism Vascular endothelial growth factor Vitamin B United States > US Kentucky
ISSN:	1932-6203, 1932-6203
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Shrnutí:	Clinical data suggests an association between systolic hypertension, renal function and hyperhomocysteinemia (HHcy). HHcy is a state of elevated plasma homocysteine (Hcy) levels and is known to cause vascular complications. In this study, we tested the hypothesis whether Ang II-induced hypertension increases plasma Hcy levels and contributes to renovascular remodeling. We also tested whether folic acid (FA) treatment reduces plasma Hcy levels by enhancing Hcy remethylation and thus mitigating renal remodeling. Hypertension was induced in WT mice by infusing Ang II using Alzet mini osmotic pumps. Blood pressure, Hcy level, renal vascular density, oxidative stress, inflammation and fibrosis markers, and angiogenic- and anti-angiogenic factors were measured. Ang II hypertension increased plasma Hcy levels and reduced renal cortical blood flow and microvascular density. Elevated Hcy in Ang II hypertension was associated with decreased 4, 5-Diaminofluorescein (DAF-2DA) staining suggesting impaired endothelial function. Increased expression of Nox-2, -4 and dihydroethidium stain revealed oxidative stress. Excess collagen IV deposition in the peri-glomerular area and increased MMP-2, and -9 expression and activity indicated renal remodeling. The mRNA and protein expression of asymmetric dimethylarginine (ADMA) was increased and eNOS protein was decreased suggesting the involvement of this pathway in Hcy mediated hypertension. Decreased expressions of VEGF and increased anti-angiogenic factors, angiostatin and endostatin indicated impaired vasculogenesis. FA treatment partially reduced hypertension by mitigating HHcy in Ang II-treated animals and alleviated pro-inflammatory, pro-fibrotic and anti-angiogenic factors. These results suggest that renovascular remodeling in Ang II-induced hypertension is, in part, due to HHcy.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Competing Interests: Co-author Utpal Sen is a PLOS ONE Editorial Board member. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. Conceived and designed the experiments: SBP US. Performed the experiments: SK. Analyzed the data: SBP US. Contributed reagents/materials/analysis tools: NM. Wrote the paper: SBP US. Animal care: NM.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0083813