Human blood pressure is dependent on balancing dietary
salt intake with its excretion by the kidney. Mendelian syndromes of altered blood pressure demonstrate the importance of the distal nephron in this process and of the
thiazide-sensitive pathway in particular.
Gordon syndrome (GS), the phenotypic inverse of the
salt-wasting
Gitelman syndrome, is a condition of hyperkalaemic
hypertension that is reversed by low-dose
thiazide diuretics or a
low-salt diet. Variants within at least four genes [i.e. with-no-
lysine(K)
kinase 1 (WNK1), WNK4, kelch-like family member 3 (KLHL3) and
cullin 3 (CUL3)] can cause the phenotype of GS. Details are still emerging for some of these genes, but it is likely that they all cause a gain-of-function in the
thiazide-sensitive Na(+) -Cl(-) cotransporter (NCC) and hence
salt retention. Herein, we discuss the key role of STE20/sporulation-specific
protein 1 (SPS1)-related
proline/
alanine-rich
kinase (SPAK), which functions as an intermediary between the WNKs and NCC and for which a loss-of-function mutation produces a Gitelman-type phenotype in a mouse model. In addition to Mendelian blood pressure syndromes, the study of patients who develop
thiazide-induced-hyponatraemia (TIH) may give further molecular insights into the role of the
thiazide-sensitive pathway for
salt reabsorption. In the present paper we discuss the key features of TIH, including its high degree of reproducibility on rechallenge, possible
genetic predisposition and mechanisms involving excessive saliuresis and water retention. Together, studies of
Gordon syndrome and TIH may increase our understanding of the molecular regulation of
sodium trafficking via the
thiazide-sensitive pathway and have important implications for hypertensive patients, both in the identification of new
antihypertensive drug targets and avoidance of hyponatraemic side-effects.