Molecular Mechanisms of Na-Cl Cotransporter in Relation to Hypertension in Chronic Kidney Disease

Abstract

Chronic kidney disease (CKD) is a common clinical disease with an increasing incidence, affecting 10 to 15% of the world’s population. Hypertension is the most common and modifiable risk factor for preventing adverse cardiovascular outcomes in patients with CKD. A survey from developed countries shows that 47% of hypertensive patients over the age of 20 have uncontrolled blood pressure (BP), and the control rate is even lower in developing countries. CKD is both a common cause of uncontrolled hypertension and a risk factor for altered sequelae. In particular, studies have demonstrated that abnormal blood-pressure patterns in CKD patients, such as non-dipping-blood-pressure patterns, are associated with a significantly increased risk of cardiovascular (CV) disease. The distal convoluted tubule (DCT) is a region of the kidney, and although only 5–10% of the sodium (Na+) filtered by the glomerulus is reabsorbed by DCT, most studies agree that Na-Cl cotransporter (NCC) in human, rabbit, mouse, and rat kidneys is the most important route of sodium reabsorption across the DCT for maintaining the homeostasis of sodium. The regulation of NCC involves a large and complex network structure, including certain physiological factors, kinases, scaffold proteins, transporter phosphorylation, and other aspects. This regulation network includes various levels. Naturally, cross-talk between the components of this system must occur in order to relay the important signals to the transporter to play its role. Knowledge of the mechanisms regulating NCC activation is critical for understanding and treating hypertension and CKD. Previous studies from our laboratory have investigated the mechanisms through which NCC is activated in several different models. In the following sections, we review the literature on the mechanisms of NCC in relation to hypertension in CKD.

التنبؤ المبكر بالاعتلال الكلوي لمرضى عراقين مصابين بالسكري النوع الثاني بدلالة تقييم بعض العوامل البيوكيمائية ذات الصلة

“…This transport appears to be stimulated by the additive effects of aldosterone and the combined actions of hyperinsulinaemia and hyperglycaemia. In addition to hyperinsulinaemia-mediated renal tubular sodium transports, it has also been suggested that the increased glomerular filtration of glucose may enhance the activity of the proximal tubular Na+glucose co-transporter and may contribute to sodium retention when decreased renal perfusion stimulation kidney produces renin enzyme 33 .This enzyme can be converting angiotensinogen to angiotensin І.. Renal endothelium produces angiotensin converting enzyme, this enzyme converts angiotensin І to angiotensin ІІ. Angiotensin ІІ acts on tubular Na reabsorption and K excretion 34 .…”

Physiological roles of chloride ions in bodily and cellular functions

“…Cl − transport can be broadly divided into active and passive transport systems. The most well-known active Cl − transporters are Na + -K + -2Cl − cotransporter (NKCC), Na + -Cl − transporter (NCC), Na + -driven Cl − /HCO 3 − exchanger (NDCBE) and K + -Cl − cotransporter (KCC) [ 62 – 65 ]. NKCC and NCC contribute to Cl − uptake into cells using electrochemical potential of Na + generated by the Na + ,K + -pump (ATPase), while NDCBE and KCC, respectively, participate in Cl − extrusion from cells using electrochemical potential of Na + and K + generated by the Na + ,K + -pump (ATPase).…”

“…WNK regulates the activity of stress-related serine-threonine kinases, STE20 (sterile 20)/SPS1-related proline/alanine-rich kinase (SPAK) and oxidative stress-responsive kinase 1 (OSR1), which are targets of WNK signaling, and consequently regulates cellular functions by modulating activities of PI3K-AKT, TGF-ß, and NF-κB [ 189 ]. WNK also regulates cation-coupled Cl − cotransporters via SPAK/OSR1 activation in renal epithelia, such as NKCC (NKCC1 and NKCC2) and KCC (KCC1—KCC4) [ 65 , 191 – 198 ], which play crucial roles in regulation of the body fluid contents and blood pressure. NKCC and KCC are also regulated by various factors including flavonoids like quercetin and myricetin [ 40 , 66 , 88 , 111 , 199 – 205 ], which also show various actions including anti-diabetic and anti-hypertensive ones [ 66 , 203 , 206 ].…”