1.
Klotho, the Holy Grail of the kidney: from salt sensitivity to chronic kidney disease.
Kalaitzidis, RG, Duni, A, Siamopoulos, KC
International urology and nephrology. 2016;(10):1657-66
Abstract
The Klotho gene displays an extremely shortened life span with loss of function missense mutations leading to premature multiple organ failure, thus resembling human premature aging syndromes. The transmembrane form of Klotho protein functions as an obligatory co-receptor for FGF23. Klotho and FGF23 are crucial components for the regulation of vitamin D metabolism and subsequently blood phosphate levels. The secreted Klotho protein has multiple regulatory functions, including effects on electrolyte homeostasis, on growth factor pathways as well as on oxidative stress, which are currently the object of extensive research. Klotho protein deficiency is observed in many experimental and clinical disease models. Genetic polymorphisms such as the G-395A polymorphism in the promoter region of the Klotho gene have been associated with the development of essential hypertension. The kidneys are the primary site of Klotho production, and renal Klotho is decreased in CKD, followed by a reduction in plasma Klotho. Klotho deficiency has been both associated with progression of CKD as well as with its cardinal systemic manifestations, including cardiovascular disease. Thus, Klotho has been suggested both as a risk biomarker for early detection of CKD and additionally as a potential therapeutic tool in the future.
2.
Advances in WNK signaling of salt and potassium metabolism: clinical implications.
Arroyo, JP, Gamba, G
American journal of nephrology. 2012;(4):379-86
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Abstract
Recent evidence due to the discovery of a family of kinases implicated in arterial hypertension now points to the underlying molecular mechanisms that dictate Na(+), K(+) and water handling in the nephron. These new key players need to be understood in order to fully comprehend the pathophysiology, manifestations, and treatment of common clinical entities such as hypovolemic shock, congestive heart failure, primary hyperaldosteronism, nephrotic syndrome and hypertension. It is through the analysis of the volume status and electrolyte abnormalities that commonly present with these diseases that we can begin to create a link between the abstract concept of a kinase regulation and how a patient will respond to a particular treatment. This review is an attempt to bridge that gap.
3.
Spotlight on renin. The renin system, salt-sensitivity and metabolic syndrome.
Fujita, T
Journal of the renin-angiotensin-aldosterone system : JRAAS. 2006;(3):181-3
4.
Role of WNK kinases in regulating tubular salt and potassium transport and in the development of hypertension.
Gamba, G
American journal of physiology. Renal physiology. 2005;(2):F245-52
Abstract
A recently discovered family of protein kinases is responsible for an autosomal-dominant disease known as Gordon's syndrome or pseudohypoaldosteronism type II (PHA-II) that features hyperkalemia and hyperchloremic metabolic acidosis, accompanied by hypertension and hypercalciuria. Four genes have been described in this kinase family, which has been named WNK, due to the absence of a key lysine in kinase subdomain II (with no K kinases). Two of these genes, WNK1 and WNK4 located in human chromosomes 12 and 17, respectively, are responsible for PHA-II. Immunohystochemical analysis revealed that WNK1 and WNK4 are predominantly expressed in the distal convoluted tubule and collecting duct. The physiological studies have shown that WNK4 downregulates the activity of ion transport pathways expressed in these nephron segments, such as the apical thiazide-sensitive Na+-Cl- cotransporter and apical secretory K+ channel ROMK, as well as upregulates paracellular chloride transport and phosphorylation of tight junction proteins such as claudins. In addition, WNK4 downregulates other Cl- influx pathways such as the basolateral Na+-K+-2Cl- cotransporter and Cl-/HCO3- exchanger. WNK4 mutations behave as a loss of function for the Na+-Cl- cotransporter and a gain of function when it comes to ROMK and claudins. These dual effects of WNK4 mutations fit with proposed mechanisms for developing electrolyte abnormalities and hypertension in PHA-II and point to WNK4 as a multifunctional regulator of diverse ion transporters.