Angiotensin II: a Candidate for High-Potassium Diet

stimulation of potassium secretion by a Angiotensin II: a candidate for high-potassium diet. Th e study by Estilo et al., when combined with the study by an aldosterone-independent Palmer and Frindt,3 indicates that there may be some potassium preservation mediator of potassium pathway that compensates for aldosterone ’ s eff ect of increasing the driving force preservation during for potassium secretion in a low-salt environment. Th is results in the appropriate volume depletion physiological response of unchanged potassium excretion in the face of a low- Robert S. Hoover 1 , 2 salt, normal-potassium diet. Th ese results suggested that there was an aldosterone- Two different stimulators of aldosterone secretion, high-potassium diet independent kaliuretic factor that was and low-sodium diet, have disparate effects on potassium secretion in stimulated by a high-potassium diet. the distal nephron. The mechanism by which the kidney preserves Th e development of potential mecha- nistic explanations of this phenomenon potassium in the face of a high-aldosterone, volume-depleted state has was aided by the molecular characteriza- engendered much thought. Yue et al. now propose that angiotensin II tion of pseudohypoaldosteronism type II inhibits the renal outer medullary potassium channel (ROMK1) through (PHAII), or familial hyperkalemic hyper- stimulation of the protein tyrosine kinase c-Src, perhaps acting as a tension. PHAII is the monogenic disorder signal to differentiate volume depletion from a high-potassium diet. of hypertension and hyperkalemia that Kidney International (2011) 79, 377 – 379. doi: 10.1038/ki.2010.476 results from mutations of the WNK (with no lysine) kinases WNK1 and WNK4. 6 Multiple studies indicate that the hypertension of this disorder is largely mediated Low-sodium diets stimulate aldosterone However, exogenously administered by hyperactivity of the sodium chloride production through activation of the aldosterone does not appear to aff ect the cotransporter (NCC). An in-depth review renin– angiotensin – aldosterone axis. Al- channel density of either ROMK1 or fl ow- of the mechanisms of WNK’ s eff ects on dosterone given exogenously stimulates stimulated BK channels in the cortical NCC is beyond the scope of this Com- urinary potassium excretion.1 Yet pa- collecting ducts (CCDs) of rats. 3 An mentary on potassium secretion and has tients (or animals) on low-salt diets do increase in potassium secretion without been undertaken many times recently. not typically develop potassium wasting an increase in the activity of potassium Suffi ce it to say that WNK1 is stimulatory and hypokalemia. High-potassium diets channels is probably secondary to the to NCC and that WNK4 may be either increase adrenal production of aldoster- well-known robust stimulation of the epi- inhibitory or stimulatory depending on one. Despite the well-known stimulation thelial sodium channel that increases the which system it is assessed in, and / or of sodium reabsorption by aldosterone, driving force for distal tubular potassium physiological conditions. WNK1 and these patients (or animals) do not typically secretion. In contrast, high-potassium WNK4 both phosphorylate and activate become hypervolemic and hypertensive. diets strongly stimulate ROMK channel the kinase Ste20-related proline / alanine- Mechanisms underlying this physiologi- activity. There are conflicting studies rich kinase (SPAK), which activates and cal conundrum have been proposed and regarding the eff ect of a low-sodium diet phosphorylates NCC. Notably, a truncated investigated (Figure 1a and b). Yue et al.2 on potassium secretion. Engbretson and kidney-specific WNK1 (KS-WNK1) propose another potential mechanism that Stoner found a diff erence in potassium seems to inhibit WNK1’ s eff ect on NCC. may allow for potassium preservation in secretion in in vitro microperfused CCDs The hyperkalemia associated with the volume-depleted patient ( Figure 1c ). of rabbits on a low-salt diet versus rabbits PHAII provides insight into the physiol- ROMK1 channels mediate basal potas- on a high-salt diet.4 However, Estilo et al. , ogy of distal tubular potassium secretion. sium secretion in the distal nephron. using similar methodology, found no dif- The full-length isoform of WNK1 ference in baseline potassium secretion in (L-WNK1) decreases the cell-surface 1Renal Division, Department of Medicine, Emory the CCDs of rabbits on a low-salt diet ver- expression of ROMK1 channels in the University , Atlanta , Georgia , USA and 2 Atlanta VA sus those on a high-salt diet.5 Importantly, Xenopus oocyte expression system. KS- Medical Center , Atlanta , Georgia , USA Engbretson and Stoner used a moderately WNK1 appears to inhibit this process, Correspondence: Robert S. Hoover, Renal Divi- sion, Department of Medicine, Emory University, high-potassium diet and then supple- resulting in increased ROMK1 channel 7 1639 Pierce Drive, WMB Suite 338, Atlanta, Georgia mented that with liquid KCl. Th us they on the cell surface. Thus a gain-of- 30322, USA. E-mail: [email protected] were essentially modeling the well-known function mutation of WNK1 would result

Kidney International (2011) 79 377 commentary

Aldo and Ang II increase WNK1 suppresses Ang II suppresses NCC activity in DCT ROMK1 in CNT and CCD ROMK1 in CNT and CCD

Apical

Basolateral + Thiazides K K+ + Cell Ang Na WNK1 c-Src Cl– Normal– AR AR Ang potassium KS–WNK1 diet SGK MR Aldo WNK4 Aldo Ang AR Na+ + Amiloride Na MR Amiloride

Figure 1 | Potential mechanisms of potassium preservation in a volume-depleted state. (a ) Aldo and Ang are secreted in a volume-depleted state, resulting in stimulation of NCC and a decrease in sodium delivery to the CNT/CCD. ( b) Under conditions of a normal-potassium diet, WNK1 is preferentially expressed over KS-WNK1, resulting in unopposed inhibition of ROMK1. A high-potassium diet would result in preferential expression of KS-WNK1 and opposition of WNK1’ s inhibition of ROMK1. ( c) Ang secretion results in stimulation of protein tyrosine kinase (such as c-SRC) and suppression of ROMK1 by two mechanisms. c-SRC directly phosphorylates ROMK1 and also opposes the effect of serum-and-glucocorticoid-inducible kinase 1 (SGK1) on WNK4. This results in release of WNK4’ s inhibitory effect on ROMK1. Note: the MR receptor is depicted here as a cell membrane receptor as opposed to its true intracellular location for ease of presentation. Aldo, aldosterone; Ang, angiotensin II; AR, angiotensin II receptor, type 1; CCD, cortical collecting duct; CNT, connecting tubule; DCT, distal convoluted tubule; MR, mineralocorticoid receptor; NCC, sodium chloride cotransporter; SGK, serum- and glucocorticoid-inducible kinase; WNK, with-no-lysine kinase. in impairment of potassium secretion a low-salt diet results in greatly decreased channels (Figure 1c). A high-potassium and hyperkalemia. It has also been pro- sodium delivery to the CNT and CCD diet suppresses angiotensin II, resulting in posed that the hyperactivity of NCC and thus decreased potassium secretion attenuation of the inhibition of ROMK1 resulting in greatly decreased sodium (Figure 1a). Th e relatively low-fl ow state and in stimulation of robust potassium delivery to the connecting tubule (CNT) would also keep BK channels inactive. secretion. Studies have indicated that and CCD is sufficient to explain the With a high-potassium, normal-sodium luminal angiotensin II inhibits potassium impairment in potassium secretion in diet, sodium delivery would be suffi cient secretion in the late distal tubule 9 and that PHAII. Th ese investigations concerning to result in robust potassium secretion in angiotensin II inhibits ROMK1 with a the pathophysiology of this process have the presence of aldosterone. Both of these low-potassium diet. 10 Yue et al. 2 now signifi cant implications for the physiol- potential mechanisms of potassium pres- present evidence that angiotensin II ogy of potassium handling in the distal ervation in the face of a hypovolemic, inhibits ROMK1 through stimulation of tubule. In fact, high-potassium diets high-aldosterone state would presumably the protein tyrosine kinase c-Src. c-Src induce increased expression of the KS- be opposed by SGK1-dependent stimula- then inhibits ROMK1 surface expression WNK1 isoform relative to the L-WNK1 tion of ROMK1 (probably by inhibition by two diff erent mechanisms: direct phos- isoform. Th is would result in increased of WNK4-mediated endocytosis of phorylation of ROMK1 at residue Y337, ROMK surface expression and secretion ROMK1) and the epithelial sodium resulting in endocytosis of ROMK, and of potassium. Th is process would pre- channel. disruption of SGK1 ’ s inhibitory eff ect on sumably be inactive with a low-salt and On the basis of their new study 2 and WNK4, allowing WNK4-mediated endo- normal-potassium diet. Th erefore, the their previous studies, Yue et al. add an cytosis of ROMK1. As SGK1 is an aldos- balance of L-WNK1 and KS-WNK1 has additional hypothesis to help explain this terone-induced protein, angiotensin II been suggested as the critical switch physiological conundrum. Th ey propose could be acting to attenuate aldosterone’ s allowing for greatly increased potassium that angiotensin II is a major mediator of eff ect on potassium secretion with low- secretion in the face of a high-potassium, the disparate eff ects on potassium secre- salt diet. Th is could explain aldosterone’ s high-aldosterone state while sparing tion produced by these two different lack of stimulation of potassium secretion potassium in a low-salt, high-aldosterone physiological milieus (high-potassium or ROMK in the CNT and CCD despite state ( Figure 1b ). Alternatively, a body of diet and low-sodium diet) that both SGK1’ s stimulation of ROMK. evidence has been amassed implicating stimulate aldosterone. In this scenario, In support of the molecular biology aldosterone as a key regulator of NCC.8 angiotensin II is activated under condi- data, the authors present animal data Th is has led to the hypothesis that the tions of a low-salt diet or volume deple- demonstrating that angio tensin II reduces strong upregulation of NCC induced by tion and acts as an inhibitor of ROMK1 potassium channel acti vity in the CCD

378 Kidney International (2011) 79 commentary

with a low-sodium diet. Patch clamp decreased, and they develop potassium 4 . Engbretson BG , Stoner LC . Flow-dependent potassium secretion by rabbit cortical collecting experiments on split-open CCDs of wasting despite angiotensin. Nonetheless, tubule in vitro . Am J Physiol Renal Physiol 1987 ; animals fed a low-sodium diet for 7 days acute preservation of potassium (less than 253 : F896 – F903 . showed a robust stimulation of ROMK 72 h) is also of great import, and all of 5 . Estilo G , Liu W , Pastor-Soler N et al. Effect of aldosterone on BK channel expression in channel activity by angiotensin. In a pre- these pathways for potassium preserva- mammalian cortical collecting duct. Am J Physiol vious study, Wei et al. demonstrated that tion are likely to be physiologically Renal Physiol 2008 ; 295 : F780 – F788 . angiotensin II inhibits ROMK channel important. 6 . Wilson FH , Disse-Nicodeme S , Choate KA et al. Human hypertension caused by mutations in WNK activity under conditions of a low-potas- DISCLOSURE kinases. Science 2001 ; 293 : 1107 – 1112 . sium diet but not under conditions of a The author declared no competing interests. 7 . Wade JB , Fang L , Liu J et al. WNK1 kinase normal-potassium diet.10 So, apparently, isoform switch regulates renal potassium excretion . Proc Natl Acad Sci USA 2006 ; 103 : not only does a high-potassium diet sup- ACKNOWLEDGMENTS 8558 – 8563 . press angiotensin II, but it also may make This work was supported by National Institute 8 . Rozansky DJ , Cornwall T , Subramanya AR et al. ROMK channels resistant to the eff ects of of Diabetes and Digestive and Kidney Diseases Aldosterone mediates activation of the thiazide- grants (R01 DK085097, K08 DK070668). sensitive Na-Cl cotransporter through an SGK1 angiotensin II. However, if angiotensin and WNK4 signaling pathway . J Clin Invest 2009 ; II-induced c-Src inhibited the eff ect of SGK REFERENCES 119: 2601 – 2612 . 1 . Horisberger JD , Diezi J . Effects of mineralocorticoids 9 . Wang T , Giebisch G . Effects of angiotensin II on on WNK4 in the distal convoluted tubule, on Na+ and K+ excretion in the adrenalectomized electrolyte transport in the early and late distal then that would result in inhibition of NCC rat. Am J Physiol Renal Physiol 1983 ; 245 : F89 – F99 . tubule in rat kidney. Am J Physiol Renal Physiol function (which clearly does not happen 2 . Yue P , Sun P , Lin D - H et al. Angiotensin II diminishes 1996 ; 271 : F143 – F149 . the effect of SGK1 on the WNK4-mediated inhibition 10 . Wei Y , Zavilowitz B , Satlin LM et al. Angiotensin with increased angiotensin II and aldoster- of ROMK1 channels. Kidney Int 2011 ; 79: 423 – 431 . II inhibits the ROMK-like small conductance K one). Th erefore, this theory requires that 3 . Palmer LG , Frindt G . Aldosterone and potassium channel in renal cortical collecting duct during c-Src is acting on the SGK1 – WNK4 inter- secretion by the cortical collecting duct. Kidney Int dietary potassium restriction. J Biol Chem 2007 ; 2000 ; 57 : 1324 – 1328 . 282: 6455 – 6462 . action only in the CNT and CCD and not in the distal convoluted tubule. Th is type of cell-specifi c eff ect is certainly possible but has yet to be proven. see original article on page 414 Th e authors astutely point out that these theories do not exclude each other, and in Nanocrystals seed calcification fact it is quite likely that multiple factors play a role in this phenomenon. Another in more ways than one potential factor to consider here is the temporal nature of these eff ects. In this Diane Proudfoot 1 and Catherine M. Shanahan 1 study the authors looked at acute eff ects of angiotensin (within minutes) in both Although much progress has been made in the past five years in their animal and their cell-culture experi- understanding the mechanisms leading to accelerated vascular ments. Aldosterone probably upregulates calcification in patients with chronic kidney disease, it remains unclear NCC over periods of days (although shorter-term effects of aldosterone on how an environment high in phosphate can impinge so significantly on NCC have not been studied). So it may be the calcification process. The study by Sage et al. highlights an important that the angiotensin II eff ect is responsible and novel role for calcium phosphate nanocrystals, produced in a high- for acute preservation of potassium in the phosphate environment, in rapidly driving calcification of vascular smooth face of a low-salt diet or volume depletion muscle cells via enhanced production of bone morphogenetic protein-2. and NCC upregulation by aldosterone is Kidney International (2011) 79, 379 – 382. doi: 10.1038/ki.2010.455 responsible for chronic preservation of potassium. It is unknown how quickly the diet-induced changes in WNK1 isoforms ELEVATED PHOSPHATE PROMOTES incidence of cardiovascular mortality. occur, but they could play an acute or VASCULAR SMOOTH MUSCLE CELL Clinical studies have demonstrated that chronic role. Th e example of Gitelman’ s CALCIFICATION elevated serum levels of phosphate (P) syndrome, in which patients have signifi - Vascular calcifi cation in patients with correlate with calcifi cation and mortal- cant potassium wasting despite chronic chronic kidney disease (CKD) is a prev- ity, and hence there have been increased angiotensin II/ aldosterone stimulation, alent condition that contributes to a high eff orts in recent years to try and estab- would argue that decreased sodium deliv- lish the mechanisms whereby elevated P ery is the primary chronic preservation 1BHF Centre of Research Excellence, Cardiovascular acts to promote vascular calcifi cation. mechanism. Because these patients lack Division, King’ s College London, London, UK Although vascular calcifi cation in CKD Correspondence: Catherine M. Shanahan, fully functional NCC, they are unable to Cardiovascular Division, King ’s College London, James was once considered an end-stage ‘ passive ’ increase NCC activity. Th erefore, sodium Black Centre, 125 Coldharbour Lane, London SE5 process of precipitation of calcium phos- delivery to the CNT and CCD cannot be 9NU, UK. E-mail: [email protected] phate (Ca / P) in the vessel wall, evidence

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