PMID- 30778103
OWN - NLM
STAT- MEDLINE
DCOM- 20200910
LR  - 20200910
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 9
IP  - 1
DP  - 2019 Feb 18
TI  - Hydrogen Sulfide Protects Hyperhomocysteinemia-Induced Renal Damage by Modulation 
      of Caveolin and eNOS Interaction.
PG  - 2223
LID - 10.1038/s41598-018-38467-6 [doi]
LID - 2223
AB  - The accumulation of homocysteine (Hcy) during chronic kidney failure (CKD) can 
      exert toxic effects on the glomeruli and tubulo-interstitial region. Among the 
      potential mechanisms, the formation of highly reactive metabolite, Hcy 
      thiolactone, is known to modify proteins by N-homocysteinylation, leading to 
      protein degradation, stress and impaired function. Previous studies documented 
      impaired nitric oxide production and altered caveolin expression in 
      hyperhomocysteinemia (HHcy), leading to endothelial dysfunction. The aim of this 
      study was to determine whether Hhcy homocysteinylates endothelial nitric oxide 
      synthase (eNOS) and alters caveolin-1 expression to decrease nitric oxide 
      bioavailability, causing hypertension and renal dysfunction. We also examined 
      whether hydrogen sulfide (H(2)S) could dehomocysteinylate eNOS to protect the 
      kidney. WT and Cystathionine beta-Synthase deficient (CBS+/-) mice representing HHcy 
      were treated without or with sodium hydrogen sulfide (NaHS), a H(2)S donor 
      (30 microM), in drinking water for 8 weeks. Hhcy mice (CBS+/-) showed low levels of 
      plasma H(2)S, elevated systolic blood pressure (SBP) and renal dysfunction. H(2)S 
      treatment reduced SBP and improved renal function. Hhcy was associated with 
      homocysteinylation of eNOS, reduced enzyme activity and upregulation of 
      caveolin-1 expression. Further, Hhcy increased extracellular matrix (ECM) protein 
      deposition and disruption of gap junction proteins, connexins. H(2)S treatment 
      reversed the changes above and transfection of triple genes producing H(2)S (CBS, 
      CSE and 3MST) showed reduction of vascular smooth muscle cell proliferation. We 
      conclude that during Hhcy, homocysteinylation of eNOS and disruption of 
      caveolin-mediated regulation leads to ECM remodeling and hypertension, and H(2)S 
      treatment attenuates renovascular damage.
FAU - Pushpakumar, Sathnur
AU  - Pushpakumar S
AD  - Department of Physiology, School of Medicine, University of Louisville, 
      Louisville, KY, 40292, USA.
FAU - Kundu, Sourav
AU  - Kundu S
AD  - Department of Botany, West Bengal State University, Berunanpukuria, Kolkata, West 
      Bengal, PIN 700126, India.
FAU - Sen, Utpal
AU  - Sen U
AD  - Department of Physiology, School of Medicine, University of Louisville, 
      Louisville, KY, 40292, USA. utpal.sen@louisville.edu.
LA  - eng
GR  - R01 DK104653/DK/NIDDK NIH HHS/United States
GR  - R01 HL104103/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190218
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Biomarkers)
RN  - 0 (Caveolins)
RN  - 0 (Connectin)
RN  - 0 (Protective Agents)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - YY9FVM7NSN (Hydrogen Sulfide)
SB  - IM
MH  - Animals
MH  - Biomarkers
MH  - Caveolins/*metabolism
MH  - Connectin/genetics/metabolism
MH  - Disease Models, Animal
MH  - Extracellular Matrix/metabolism
MH  - Gene Expression
MH  - Hydrogen Sulfide/*metabolism/pharmacology
MH  - Hyperhomocysteinemia/*complications
MH  - Kidney Diseases/diagnosis/drug therapy/*etiology/*metabolism
MH  - Kidney Function Tests
MH  - Mice
MH  - Myocytes, Smooth Muscle/drug effects/metabolism
MH  - Nitric Oxide/metabolism
MH  - Nitric Oxide Synthase Type III/*metabolism
MH  - Protective Agents/*metabolism/pharmacology
MH  - Protein Binding
PMC - PMC6379383
COIS- The authors declare no competing interests.
EDAT- 2019/02/20 06:00
MHDA- 2020/09/12 06:00
PMCR- 2019/02/18
CRDT- 2019/02/20 06:00
PHST- 2018/09/03 00:00 [received]
PHST- 2018/12/19 00:00 [accepted]
PHST- 2019/02/20 06:00 [entrez]
PHST- 2019/02/20 06:00 [pubmed]
PHST- 2020/09/12 06:00 [medline]
PHST- 2019/02/18 00:00 [pmc-release]
AID - 10.1038/s41598-018-38467-6 [pii]
AID - 38467 [pii]
AID - 10.1038/s41598-018-38467-6 [doi]
PST - epublish
SO  - Sci Rep. 2019 Feb 18;9(1):2223. doi: 10.1038/s41598-018-38467-6.