Regulatory control of the Na-Cl co-transporter NCC and its therapeutic potential for hypertension.
10.1016/j.apsb.2020.09.009
- Author:
Nur Farah MEOR AZLAN
1
;
Maarten P KOENERS
1
;
Jinwei ZHANG
1
Author Information
1. Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Hatherly Laboratories, Exeter EX4 4PS, UK.
- Publication Type:Review
- Keywords:
ATP, adenosine triphosphate;
Blood pressure regulation;
CCC, cation-coupled chloride cotransporters;
CCT, conserved carboxy-terminal;
CNI, calcineurin inhibitors;
CUL3, cullin 3;
CUL3/KLHL3-WNK-SPAK/OSR1;
Ca2+, calcium ion;
Cardiovascular disease;
DAG, diacylglycerol;
DCT, distal convoluted tubule;
DUSP, dual specificity phosphatases;
ECF, extracellular fluid;
ELISA, enzyme-bound immunosorbent analysis;
ERK, extracellular signal-regulated kinases;
EnaC, epithelial sodium channels;
GABA, gamma-aminobutyric acid;
HEK293, human embryonic kidney 293;
Hypertension;
I1, inhibitor 1;
K+, potassium ion;
KCC, potassium-chloride-cotransporters;
KLHL3, kelch-like 3;
KS-WNK1, kidney specific-WNK1;
Kinase inhibitors;
MAPK, mitogen-activated protein kinase;
MO25, mouse protein-25;
Membrane trafficking;
NCC, sodium–chloride cotransporters;
NKCC, sodium–potassium–chloride-cotransporter;
Na+, sodium ion;
NaCl, sodium chloride;
NaCl-cotransporter NCC;
OSR1, oxidative stress-responsive gene 1;
PCT, proximal convoluted tubule;
PHAII, pseudohypoaldosteronism type II;
PP, protein phosphatase;
PV, parvalbumin;
ROMK, renal outer medullary potassium;
RasGRP1, RAS guanyl-releasing protein 1;
SLC12, solute carrier 12;
SPAK, Ste20-related proline-alanine-rich-kinase;
TAL, thick ascending limb;
Therapeutic targets;
WNK, with-no-lysine kinases;
mDCT, mammalian DCT;
mRNA, messenger RNA
- From:
Acta Pharmaceutica Sinica B
2021;11(5):1117-1128
- CountryChina
- Language:English
-
Abstract:
Hypertension is the largest risk factor for cardiovascular disease, the leading cause of mortality worldwide. As blood pressure regulation is influenced by multiple physiological systems, hypertension cannot be attributed to a single identifiable etiology. Three decades of research into Mendelian forms of hypertension implicated alterations in the renal tubular sodium handling, particularly the distal convoluted tubule (DCT)-native, thiazide-sensitive Na-Cl cotransporter (NCC). Altered functions of the NCC have shown to have profound effects on blood pressure regulation as illustrated by the over activation and inactivation of the NCC in Gordon's and Gitelman syndromes respectively. Substantial progress has uncovered multiple factors that affect the expression and activity of the NCC. In particular, NCC activity is controlled by phosphorylation/dephosphorylation, and NCC expression is facilitated by glycosylation and negatively regulated by ubiquitination. Studies have even found parvalbumin to be an unexpected regulator of the NCC. In recent years, there have been considerable advances in our understanding of NCC control mechanisms, particularly
