title: Functional coupling of renal K+ and Na+ handling causes high blood pressure in Na+ replete mice.
abstract: A network of kinases, including WNKs, SPAK and Sgk1, is critical for the independent regulation of K+ and Na+ transport in the distal nephron. Angiotensin II is thought to act as a key hormone in orchestrating these kinases to switch from K+ secretion during hyperkalaemia to Na+ reabsorption during intravascular volume depletion, thus keeping disturbances in electrolyte and blood pressure homeostasis at a minimum. It remains unclear, however, how K+ and Na+ transport are regulated during a high Na+ intake, which is associated with suppressed angiotensin II levels and a high distal tubular Na+ load. We therefore investigated the integrated blood pressure, renal, hormonal and gene and protein expression responses to large changes of K+ intake in Na+ replete mice. Both low and high K+ intake increased blood pressure and caused Na+ retention. Low K+ intake was accompanied by an upregulation of the sodium-chloride cotransporter (NCC) and its activating kinase SPAK, and inhibition of NCC normalized blood pressure. Renal responses were unaffected by angiotensin AT1 receptor antagonism, indicating that low K+ intake activates the distal nephron by an angiotensin-independent mode of action. High K+ intake was associated with elevated plasma aldosterone concentrations and an upregulation of the epithelial sodium channel (ENaC) and its activating kinase Sgk1. Surprisingly, high K+ intake increased blood pressure even during ENaC or mineralocorticoid receptor antagonism, suggesting the contribution of aldosterone-independent mechanisms. These findings show that in a Na+ replete state, changes in K+ intake induce specific molecular and functional adaptations in the distal nephron that cause a functional coupling of renal K+ and Na+ handling, resulting in Na+ retention and high blood pressure when K+ intake is either restricted or excessively increased.
authors.affiliation: Department of Cellular and Integrative Physiology, Centre for Experimental Medicine, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. ehmke@uke.uni-hamburg.de.
authors.forename: Helga
authors.initials: H
authors.lastname: Vitzthum
authors.forename: Anika
authors.initials: A
authors.lastname: Seniuk
authors.forename: Laura Helene
authors.initials: LH
authors.lastname: Schulte
authors.forename: Maxie Luise
authors.initials: ML
authors.lastname: Müller
authors.forename: Hannah
authors.initials: H
authors.lastname: Hetz
authors.forename: Heimo
authors.initials: H
authors.lastname: Ehmke
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D006947:Hyperkalemia / Q000503:physiopathology*; D006977:Hypertension, Renal / Q000503:physiopathology*; D007668:Kidney / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011188:Potassium / Q000378:metabolism*; D017419:Potassium, Dietary / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D012982:Sodium, Dietary / Q000378:metabolism*
chemical_list: D017419:Potassium, Dietary; D012982:Sodium, Dietary; D000450:Aldosterone; D012964:Sodium; D011188:Potassium