Hyperkalemia and blood pressure regulation.
TL;DR: Recent progress in understanding WNK signalling is summarized, an update of available models for renal adaptation to hyperkalemic conditions is presented, and pharmacological targeting of WNKs or their substrates offers promising options to manage hypertension while preventinghyperkalemia.
Abstract: Hypertension is common in the general population. Management of hypertensive patients at risk of hyperkalemia is challenging due to potential life-threatening complications such as cardiac arrest. Chronic hyperkalemia is often associated with impaired renal ability to excrete excessive potassium ions (K+). This may refer to chronic kidney disease or certain pharmacological interventions, including broadly used renin-angiotensin-aldosterone system and calcineurin inhibitors. Understanding the intrinsic mechanisms permitting kidney adaptations to hyperkalemia is critical for choosing therapeutic strategies. Valuable insights were obtained from the analysis of familial hyperkalemic hypertension (FHHt) syndrome, which became a classic model for coincidence of high blood pressure and hyperkalemia. FHHt can be caused by mutations in several genes, all of them resulting in excessive activity of with-no-lysine kinases (WNKs) in the distal nephron of the kidney. WNKs have been increasingly recognized as key signalling enzymes in the regulation of renal sodium ions (Na+) and K+ handling, enabling adaptive responses to systemic shifts of potassium homoeostasis consequent to variations in dietary potassium intake or disease. The WNK signalling pathway recruits a complex protein network mediating catalytic and non-catalytic effects of distinct WNK isoforms on relevant Na+- or K+-transporting proteins. In this review article, we summarize recent progress in understanding WNK signalling. An update of available models for renal adaptation to hyperkalemic conditions is presented. Consequences for blood pressure regulation are discussed. Pharmacological targeting of WNKs or their substrates offers promising options to manage hypertension while preventing hyperkalemia.
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TL;DR: In this article, the authors investigated the involvement of kelch-like protein 3 (KLHL3)-Cullin3 complex was identified as an E3 ubiquitin ligase for with no lysine (WNK) kinases, and the impaired ubiquitination of WNK4 causes pseudohypoaldosteronism type II (PHAII), a hereditary hypertensive disease.
Abstract: Recently, the kelch-like protein 3 (KLHL3)-Cullin3 complex was identified as an E3 ubiquitin ligase for with no lysine (WNK) kinases, and the impaired ubiquitination of WNK4 causes pseudohypoaldosteronism type II (PHAII), a hereditary hypertensive disease. However, the involvement of WNK kinase regulation by ubiquitination in situations other than PHAII has not been identified. Previously, we identified the WNK3-STE20/SPS1-related proline/alanine-rich kinase-Na/K/Cl cotransporter isoform 1 phosphorylation cascade in vascular smooth muscle cells and found that it constitutes an important mechanism of vascular constriction by angiotensin II (AngII). In this study, we investigated the involvement of KLHL proteins in AngII-induced WNK3 activation of vascular smooth muscle cells. In the mouse aorta and mouse vascular smooth muscle (MOVAS) cells, KLHL3 was not expressed, but KLHL2, the closest homolog of KLHL3, was expressed. Salt depletion and acute infusion of AngII decreased KLHL2 and increased WNK3 levels in the mouse aorta. Notably, the AngII-induced changes in KLHL2 and WNK3 expression occurred within minutes in MOVAS cells. Results of KLHL2 overexpression and knockdown experiments in MOVAS cells confirmed that KLHL2 is the major regulator of WNK3 protein abundance. The AngII-induced decrease in KLHL2 was not caused by decreased transcription but increased autophagy-mediated degradation. Furthermore, knockdown of sequestosome 1/p62 prevented the decrease in KLHL2, suggesting that the mechanism of KLHL2 autophagy could be selective autophagy mediated by sequestosome 1/p62. Thus, we identified a novel component of signal transduction in AngII-induced vascular contraction that could be a promising drug target.
19 citations
TL;DR: In this paper, furosemide is shown to be a k-sparing diuretic by decreasing the TAL net K+ secretion in subjects on low-Na, high-K diet.
Abstract: Because of its cardio-protective effects, a low-Na, high-K diet (LNaHK) is often warranted in conjunction with diuretics to treat hypertensive patients. However, it is necessary to understand the renal handling of such diets in order to choose the best diuretic. Wild-type (WT) or Renal Outer Medullary K channel (ROMK) knockout mice (KO) were given a regular (CTRL), LNaHK, or high-K diet (HK) for 4-7 days. On LNaHK, mice treated with either IP furosemide for 12 hrs, or given furosemide in drinking water for 7 days, exhibited decreased K clearance. We used free-flow micropuncture to measure the [K+] in the early distal tubule (EDT [K+]) before and after furosemide treatment. Furosemide increased the EDT [K+] in WT on CTRL but decreased that in WT on LNaHK. Furosemide did not affect the EDT [K+] of KO on LNaHK or WT on HK. Furosemide-sensitive Na+ excretion was significantly greater in mice on LNaHK than those on CTRL or HK. Patch clamp analysis of split-open TALs revealed that 70-pS ROMK exhibited a higher open probability (Po) but similar density in mice on LNaHK, compared with CTRL. No difference was found in the density or Po of the 30 pS K channels between the two groups. These results indicate mice on LNaHK exhibited furosemide-sensitive net K+ secretion in the TAL that is dependent on increased NKCC2 activity and mediated by ROMK. We conclude that furosemide is a K-sparing diuretic by decreasing the TAL net K+ secretion in subjects on LNaHK.
2 citations
TL;DR: Patiromer, a new oral potassium-binding agent, has been approved for clinical use in several countries, including Europe and US as discussed by the authors, has demonstrated that patiromer is effective in inducing a rapid and sustained K+ reduction in various patient settings, including those where RAASIs are a fundamental component of cardiorenal protection.
Abstract: Hyperkalemia is an elevated level of serum potassium (K+) and does represent a life-threatening condition. In clinical practice, hyperkalemia mainly derives from an impaired renal K+ excretion which, in turn, is usually caused by either acute or chronic renal failure. In concordance with this, hyperkalemia is very common in several chronic conditions, such as kidney disease, diabetes mellitus, heart failure, hypertension, and coronary heart disease. In all of these conditions the use of Renin–Angiotensin–Aldosterone System inhibitors (RAASIs), such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonist is widely recommended and further increases the risk of hyperkalemia. As hypertension is concerned, clinical trials suggest that the risk of hyperkalemia associated with RAASIs ranges from 2 to 10%. This often leads to a reduction or complete cessation of RAASIs, leaving patients without protective medications. Patiromer, a new oral potassium-binding agent, has been approved for clinical use in several countries, including Europe and US. Clinical studies have demonstrated that patiromer is effective in inducing a rapid and sustained K+ reduction in various patient settings, including those where RAASIs are a fundamental component of cardiorenal protection. Patiromer is generally well tolerated and characterised by a good safety profile. Most importantly, patiromer use might allow the continuation of ACEIs and ARBs in hypertensive patients developing hyperkalemia during treatment and thereby favour a more effective and long-lasting cardiorenal protection.
2 citations
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TL;DR: Two genes causing pseudohypoaldosteronism type II, a Mendelian trait featuring hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion are identified.
Abstract: Hypertension is a major public health problem of largely unknown cause. Here, we identify two genes causing pseudohypoaldosteronism type II, a Mendelian trait featuring hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Both genes encode members of the WNK family of serine-threonine kinases. Disease-causing mutations in WNK1 are large intronic deletions that increase WNK1 expression. The mutations in WNK4 are missense, which cluster in a short, highly conserved segment of the encoded protein. Both proteins localize to the distal nephron, a kidney segment involved in salt, K+, and pH homeostasis. WNK1 is cytoplasmic, whereas WNK4 localizes to tight junctions. The WNK kinases and their associated signaling pathway(s) may offer new targets for the development of antihypertensive drugs.
1,363 citations
TL;DR: The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cycloporine or tacolimus could be more important than systemic exposure.
Abstract: The use of the calcineurin inhibitors cyclosporine and tacrolimus led to major advances in the field of transplantation, with excellent short-term outcome. However, the chronic nephrotoxicity of these drugs is the Achilles' heel of current immunosuppressive regimens. In this review, the authors summarize the clinical features and histologic appearance of both acute and chronic calcineurin inhibitor nephrotoxicity in renal and nonrenal transplantation, together with the pitfalls in its diagnosis. The authors also review the available literature on the physiologic and molecular mechanisms underlying acute and chronic calcineurin inhibitor nephrotoxicity, and demonstrate that its development is related to both reversible alterations and irreversible damage to all compartments of the kidneys, including glomeruli, arterioles, and tubulo-interstitium. The main question--whether nephrotoxicity is secondary to the actions of cyclosporine and tacrolimus on the calcineurin-NFAT pathway--remains largely unanswered. The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cyclosporine or tacrolimus could be more important than systemic exposure. Finally, other local susceptibility factors for calcineurin inhibitor nephrotoxicity are reviewed, including variability in P-glycoprotein and CYP3A4/5 expression or activity, older kidney age, salt depletion, the use of nonsteroidal anti-inflammatory drugs, and genetic polymorphisms in genes like TGF-beta and ACE. Better insight into the mechanisms underlying calcineurin inhibitor nephrotoxicity might pave the way toward more targeted therapy or prevention of calcineurin inhibitor nephrotoxicity.
1,228 citations
TL;DR: It is speculated that a wide variety of non-conservative mutations, consistent with loss of function alleles, in affected subjects lead to reduced sodium chloride reabsorption in the more common heterozygotes, potentially protecting against development of hypertension.
Abstract: Maintenance of fluid and electrolyte homeostasis is critical for normal neuromuscular function Bartter's syndrome is an autosomal recessive disease characterized by diverse abnormalities in electrolyte homeostasis including hypokalaemic metabolic alkalosis; Gitelman's syndrome represents the predominant subset of Bartter's patients having hypomagnesemia and hypocalciuria We now demonstrate complete linkage of Gitelman's syndrome to the locus encoding the renal thiazide-sensitive Na–Cl cotransporter, and identify a wide variety of non-conservative mutations, consistent with loss of function alleles, in affected subjects These findings demonstrate the molecular basis of Gitelman's syndrome We speculate that these mutant alleles lead to reduced sodium chloride reabsorption in the more common heterozygotes, potentially protecting against development of hypertension
1,140 citations
TL;DR: Examination of the ROMK gene reveals mutations that co–segregate with the disease and disrupt ROMK function in four Bartter's kindreds, establishing the genetic heterogeneity of Bartter’s syndrome and demonstrating the physiologic role of ROMK in vivo.
Abstract: Mutations in the Na-K-2Cl cotransporter (NKCC2), a mediator of renal salt reabsorption, cause Bartter's syndrome, featuring salt wasting, hypokalaemic alkalosis, hypercalciuria and low blood pressure. NKCC2 mutations can be excluded in some Bartter's kindreds, prompting examination of regulators of cotransporter activity. One regulator is believed to be ROMK, an ATP-sensitive K+ channel that 'recycles' reabsorbed K+ back to the tubule lumen. Examination of the ROMK gene reveals mutations that co-segregate with the disease and disrupt ROMK function in four Bartter's kindreds. Our findings establish the genetic heterogeneity of Bartter's syndrome, and demonstrate the physiologic role of ROMK in vivo.
776 citations
TL;DR: This review examines epidemiologic, physiological, and molecular evidence that the interplay between sodium and potassium is central to the development of hypertension and makes recommendations for reducing sodium and increasing potassium in the diet.
Abstract: This review examines epidemiologic, physiological, and molecular evidence that the interplay between sodium and potassium is central to the development of hypertension. The review concludes with recommendations for reducing sodium and increasing potassium in the diet.
711 citations