PMID- 24386282
OWN - NLM
STAT- MEDLINE
DCOM- 20140831
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 12
DP  - 2013
TI  - Folic acid mitigates angiotensin-II-induced blood pressure and renal remodeling.
PG  - e83813
LID - 10.1371/journal.pone.0083813 [doi]
LID - e83813
AB  - 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.
FAU - Pushpakumar, Sathnur B
AU  - Pushpakumar SB
AD  - Department of Physiology and Biophysics, University of Louisville School of 
      Medicine, Louisville, Kentucky, United States of America.
FAU - Kundu, Sourav
AU  - Kundu S
AD  - Department of Physiology and Biophysics, University of Louisville School of 
      Medicine, Louisville, Kentucky, United States of America.
FAU - Metreveli, Naira
AU  - Metreveli N
AD  - Department of Physiology and Biophysics, University of Louisville School of 
      Medicine, Louisville, Kentucky, United States of America.
FAU - Sen, Utpal
AU  - Sen U
AD  - Department of Physiology and Biophysics, University of Louisville School of 
      Medicine, Louisville, Kentucky, United States of America.
LA  - eng
GR  - R01 HL104103/HL/NHLBI NIH HHS/United States
GR  - HL-104103/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20131226
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (RNA, Messenger)
RN  - 0 (Tissue Inhibitor of Metalloproteinases)
RN  - 0 (dimethylarginine)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 11128-99-7 (Angiotensin II)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 9007-34-5 (Collagen)
RN  - 935E97BOY8 (Folic Acid)
RN  - 94ZLA3W45F (Arginine)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - EC 3.4.24.- (Matrix Metalloproteinases)
SB  - IM
MH  - Angiotensin II/*pharmacology
MH  - Animals
MH  - Arginine/analogs & derivatives/metabolism
MH  - Blood Pressure/*drug effects
MH  - Collagen/metabolism
MH  - Drinking/drug effects
MH  - Folic Acid/*pharmacology
MH  - Gene Expression Regulation, Enzymologic/drug effects
MH  - Homocysteine/blood
MH  - Hyperhomocysteinemia/complications
MH  - Hypertension/chemically induced/complications/metabolism/physiopathology
MH  - Kidney/physiopathology
MH  - Matrix Metalloproteinases/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Nitric Oxide/biosynthesis
MH  - Nitric Oxide Synthase Type III/metabolism
MH  - RNA, Messenger/genetics/metabolism
MH  - Tissue Inhibitor of Metalloproteinases/metabolism
PMC - PMC3873386
COIS- 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.
EDAT- 2014/01/05 06:00
MHDA- 2014/09/01 06:00
PMCR- 2013/12/26
CRDT- 2014/01/04 06:00
PHST- 2013/03/08 00:00 [received]
PHST- 2013/11/08 00:00 [accepted]
PHST- 2014/01/04 06:00 [entrez]
PHST- 2014/01/05 06:00 [pubmed]
PHST- 2014/09/01 06:00 [medline]
PHST- 2013/12/26 00:00 [pmc-release]
AID - PONE-D-13-09975 [pii]
AID - 10.1371/journal.pone.0083813 [doi]
PST - epublish
SO  - PLoS One. 2013 Dec 26;8(12):e83813. doi: 10.1371/journal.pone.0083813. 
      eCollection 2013.