Kidney and blood pressure regulation-latest evidence for molecular mechanisms

Abstract

Hypertension is one of the major health problems leading to the development of cardiovascular diseases. Despite a rapid expansion in global hypertension prevalence, molecular mechanisms leading to hypertension are not fully understood largely due to the complexity of pathogenesis involving several factors. Salt intake is recognized as a leading determinant of blood pressure, since reduced dietary salt intake is related to lower morbidity and mortality, and hypertension in relation to cardiovascular events. Compared with salt-resistant populations, salt-sensitive individuals exhibit high sensitivity in blood pressure responses according to changes in salt intake. In this setting, the kidney plays a major role in the maintenance of blood pressure under the hormonal control of the renin-angiotensin-aldosterone system. In the present review, we summarize the current overview on the molecular mechanisms for modulation of blood pressure associated with renal ion channels/transporters including sodium-hydrogen exchanger isoform 3 (NHE3), Na⁺-K⁺-2Cl^- cotransporter (NKCC2), sodium-chloride cotransporter (NCC), epithelial sodium channel (ENaC) and pendrin expressed in different nephron segments. In particular, recent studies on experimental animal models with deletion of renal ion channels led to the identification of several crucial physiological mechanisms and molecules involved in hypertension. These findings could further provide a potential for novel therapeutic approaches applicable on human patients with hypertension.

Keywords: blood pressure regulation; hypertension; renal salt transport; renin–angiotensin–aldosterone system (RAAS).

Figure 1:

Sodium transporters, exchangers and ion channels along the nephron. NHE3, sodium-hydrogen exchanger isoform 3; Napi-2a, sodium-phosphate cotransporter 2a; SGLT2, sodium-glucose cotransporter; NKCC2, Na⁺-K⁺-2Cl⁻ cotransporter; ROMK, renal outer medullary potassium channel; ClC-Kb, chloride channel Kb; NCC, sodium-chloride cotransporter; Kir4.1, inward-rectifying potassium channel 4.1; ENaC, epithelial sodium channel; NDCBE, sodium-driven chloride/bicarbonate exchanger; vH⁺-ATPase, vacuolar H⁺-ATPase.

Figure 2:

Rare genetic blood pressure disorders associated with mutations in genes encoding sodium transporters, exchangers, ion channels and their regulators expressed along the nephron.

Figure 3:

Sodium transporters, exchangers and ion channels along the nephron of MHS at pre-hypertensive phase (23–25 days old) [65]. Although NKCC2 at TAL is significantly enhanced (red thick arrow), MHS at this age retains comparable blood pressure with respect to MNS presumably due to the compensatory mechanism involving downregulation of NCC and ENaC (red dashed arrow) at the downstream nephron segments.

Figure 4:

Sodium transporters, exchangers and ion channels along the nephron of MHS at 3 months old [67]. At this stage, MHS develops hypertension due to the marked upregulation of NCC in conjunction with ClC-Kb (red thick arrows). Increased phosphorylation of NKCC2 at TAL is also implicated in the pathogenesis of hypertension in this strain [68].