PMID- 36359330
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20221126
IS  - 2227-9059 (Print)
IS  - 2227-9059 (Electronic)
IS  - 2227-9059 (Linking)
VI  - 10
IP  - 11
DP  - 2022 Nov 4
TI  - Inverse Salt Sensitivity of Blood Pressure Is Associated with an Increased 
      Renin-Angiotensin System Activity.
LID - 10.3390/biomedicines10112811 [doi]
LID - 0
AB  - High and low sodium diets are associated with increased blood pressure and 
      cardiovascular morbidity and mortality. The paradoxical response of elevated BP 
      in low salt diets, aka inverse salt sensitivity (ISS), is an understudied 
      vulnerable 11% of the adult population with yet undiscovered etiology. A linear 
      relationship between the number of single nucleotide polymorphisms (SNPs) in the 
      dopamine D(2) receptor (DRD2, rs6276 and 6277), and the sodium myo-inositol 
      cotransporter 2 (SLC5A11, rs11074656), as well as decreased expression of these 
      two genes in urine-derived renal proximal tubule cells (uRPTCs) isolated from 
      clinical study participants suggest involvement of these cells in ISS. Insight 
      into this newly discovered paradoxical response to sodium is found by incubating 
      cells in low sodium (LS) conditions that unveil cell physiologic differences that 
      are then reversed by mir-485-5p miRNA blocker transfection and bypassing the 
      genetic defect by DRD2 re-expression. The renin-angiotensin system (RAS) is an 
      important counter-regulatory mechanism to prevent hyponatremia under LS 
      conditions. Oversensitive RAS under LS conditions could partially explain the 
      increased mortality in ISS. Angiotensin-II (AngII, 10 nmol/L) increased sodium 
      transport in uRPTCs to a greater extent in individuals with ISS than SR. 
      Downstream signaling of AngII is verified by identifying lowered expression of 
      nuclear factor erythroid 2-related factor 2 (NRF2), CCCTC-binding factor (CTCF), 
      and manganese-dependent mitochondrial superoxide dismutase (SOD2) only in 
      ISS-derived uRPTCs and not SR-derived uRPTCs when incubated in LS conditions. We 
      conclude that DRD2 and SLC5A11 variants in ISS may cause an increased low sodium 
      sensitivity to AngII and renal sodium reabsorption which can contribute to 
      inverse salt-sensitive hypertension.
FAU - Gildea, John J
AU  - Gildea JJ
AD  - Department of Pathology, The University of Virginia, Charlottesville, VA 22903, 
      USA.
FAU - Xu, Peng
AU  - Xu P
AD  - Department of Pathology, The University of Virginia, Charlottesville, VA 22903, 
      USA.
FAU - Schiermeyer, Katie A
AU  - Schiermeyer KA
AD  - Department of Pathology, The University of Virginia, Charlottesville, VA 22903, 
      USA.
FAU - Yue, Wei
AU  - Yue W
AD  - Department of Pathology, The University of Virginia, Charlottesville, VA 22903, 
      USA.
FAU - Carey, Robert M
AU  - Carey RM
AD  - Division of Endocrinology and Metabolism, Department of Medicine, The University 
      of Virginia, Charlottesville, VA 22903, USA.
FAU - Jose, Pedro A
AU  - Jose PA
AD  - Division of Renal Diseases & Hypertension, Department of Medicine, School of 
      Medicine and Health Sciences, The George Washington University, Washington, DC 
      20052, USA.
AD  - Department of Physiology/Pharmacology, School of Medicine and Health Sciences, 
      The George Washington University, Washington, DC 20052, USA.
FAU - Felder, Robin A
AU  - Felder RA
AUID- ORCID: 0000-0003-2797-4289
AD  - Department of Pathology, The University of Virginia, Charlottesville, VA 22903, 
      USA.
LA  - eng
GR  - P01 HL074940/HL/NHLBI NIH HHS/United States
GR  - R01 HL128189/HL/NHLBI NIH HHS/United States
GR  - DK119652/DK/NIDDK NIH HHS/United States
GR  - DK039308/DK/NIDDK NIH HHS/United States
PT  - Journal Article
DEP - 20221104
PL  - Switzerland
TA  - Biomedicines
JT  - Biomedicines
JID - 101691304
PMC - PMC9687845
OTO - NOTNLM
OT  - angiotensin
OT  - dopamine
OT  - dopamine receptor
OT  - inverse salt sensitivity
OT  - salt resistance
OT  - saltsensitivity
COIS- The authors declare no conflict of interest.
EDAT- 2022/11/12 06:00
MHDA- 2022/11/12 06:01
PMCR- 2022/11/04
CRDT- 2022/11/11 01:10
PHST- 2022/10/14 00:00 [received]
PHST- 2022/10/30 00:00 [revised]
PHST- 2022/10/31 00:00 [accepted]
PHST- 2022/11/11 01:10 [entrez]
PHST- 2022/11/12 06:00 [pubmed]
PHST- 2022/11/12 06:01 [medline]
PHST- 2022/11/04 00:00 [pmc-release]
AID - biomedicines10112811 [pii]
AID - biomedicines-10-02811 [pii]
AID - 10.3390/biomedicines10112811 [doi]
PST - epublish
SO  - Biomedicines. 2022 Nov 4;10(11):0. doi: 10.3390/biomedicines10112811.