Presse Re´nale

New Approaches to Pathogenesis and Management of Hypertension

Eberhard Ritz Medizinische Klinik/Sektion Nephrologie, Klinikum der Universitat/Heidelberg, Heidelberg, Germany Clin J Am Soc Nephrol 4: 1886–1891, 2009. doi: 10.2215/CJN.07561009

Catheter-based renal sympathetic renal tissue damage such as injection of minute volumes of denervation for resistant hypertension: A phenol, trigger afferent signals that ascend via the spinal cord to multicenter safety and proof-of-principle the posterior hypothalamus, resulting in increased efferent cohort study. Lancet 373: 1275–1281, 2009 sympathetic activity (8,9). Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski In the distant past, it had been assumed that sympathetic acti- J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, vation is restricted to advanced kidney disease and the presence of Abraham WT, Esler M uremic toxins. Increased sympathetic activity had been docu- mented by the methodologic gold standard of microneurography Upon the initiative of Smithwick and Thompson (1) of the Mas- in end-stage kidney disease but later on also in earlier stages of sachusetts General Hospital, resection of the splanchnic nerves chronic kidney disease (11,12). It is interesting that after renal through a posterior infradiaphragmatic approach plus removal of transplantation BP decreases and microneurographic overactivity the sympathetic chain from the level of the eighth dorsal ganglion is normalized when the recipient’s own anuric kidneys are re- to the second lumbar ganglion had been used with relative fre- moved by bilateral nephrectomy, clearly illustrating the important quency in cases of desperate hypertension at the time when anti- role of the kidney independent of its excretory function (13). A hypertensive medication was not yet available. In the hands of new twist has been introduced by the recognition that the kidney other investigators, the results were spectacular in a minority of secretes a proform of an enzyme called renalase, which retards patients but not quite satisfactory in many patients (2,3). Despite catecholamine breakdown (14). The complexity of sympathetic improvement of headache, reversal of papilledema in malignant activation in chronic renal failure was recently reviewed by hypertension, etc., the long-term reduction of BP was quite vari- Schlaich et al. (10). able and the 5-yr mortality remained approximately 40% (2). A There is little argument about Guyton and Coleman’s postulate 10-yr follow-up compared 100 patients who were subjected to that “all forms of hypertension are ultimately a consequence of thoracolumbar sympathectomy with 1500 patients who received resetting of the pressure-natriuresis relationship” (15). This con- symptomatic therapy. Lasting BP reduction was seen only in one cept is supported by observations such as that transplantation of a third of the patients (4). Whereas the average BP levels were reduced, occasional BP spikes were not. The average difference of kidney from a donor with normotension causes persistent normo- preoperative to postoperative systolic BP values was 21 mmHg. tension in the recipient, that high urinary albumin excretion pre- The authors saw reduction of cerebrovascular accidents and less cedes the onset of overt hypertension, that patients with essential progression of proteinuria and renal dysfunction, but 10-yr mor- hypertension have fewer nephrons, and that asymptomatic het- tality was still 41%. Against this background, once effective anti- erozygotic carriers of the Gitelman mutation have lower BP than hypertensive medication was available, this relatively crude pro- the background population (Mendelian randomization) (16–19). cedure fell out of favor and remained a sleeping beauty. Apart from these observations, however, there is good evidence With today’s better insight into the role of sympathetic ac- that renal sympathetic activity is also crucial for the initiation and tivity in the genesis of hypertension and particularly the role of maintenance of systemic hypertension even in the absence of the kidney in sympathetic activation, there has been a renais- kidney disease (5,20,21). Young humans with borderline hyper- sance in the interest of the renal sympathetic nervous system, tension exhibit already increased norepinephrine spillover, an including its role in primary hypertension—apart from its un- index of sympathetic nerve activity, in the kidney (22). Barajas and doubted role in the hypertension of chronic kidney disease Muller (23) found in experimental studies that bilateral renal (5–10). Renal disease and, in animal experiments, even minor denervation prevented the development or attenuated the mag- nitude of hypertension. Sympathetic activity affects a great spec- trum of renal functions, for example, increasing renal tubular sodium reabsorption independent of changes in GFR by releasing Published online ahead of print. Publication date available at www.cjasn.org. norepinephrine and stimulating postsynaptic ␣-1 adrenal recep- Correspondence: Dr. Eberhard Ritz, Department of Internal Medicine, Division of tors on the basolateral membrane of renal tubular epithelial cells Nephrology, Nirenzentrum, Im Neuenheimer Feld 162, D-69120 Heidelberg, Ger- many. Phone: ϩ49 (0) 6221 601705 or ϩ49 (0) 6221 189976; Fax: ϩ49 (0) 6221 603302; (24). E-mail: [email protected] Hypertension control remains poor worldwide, and one partic-

Copyright © 2009 by the American Society of Nephrology ISSN: 1555-9041/412–1886 Clin J Am Soc Nephrol 4: 1886–1891, 2009 Presse Re´nale 1887 ular problem is the management of “resistant hypertension” de- (26,30). It is also of note that not all patients responded, fined as hypertensive BP values despite use of three antihyper- suggesting heterogeneity of the role of sympathetic overac- tensive agents, including a diuretic (25). Past efforts to correct this tivity in the genesis of resistant hypertension. The challenge condition included administration of the mineralocorticoid recep- in the future will be to provide long-term controlled data on tor antagonist spironolactone, which lowered BP on average by safety (particularly in less experienced hands) and quantifi- 21.9/9.5 mmHg in the Anglo-Scandinavian Cardiac Outcomes cation of the efficacy compared with proven treatments in Trial (ASCOT) study (26). As a procedure competing with the resistant hypertension and to work out criteria to identify approach described next, carotid baroreceptor stimulation is un- nonresponders (26,30). der investigation as well (27,28). References In view of the aforementioned important role of the renal 1. Smithwick RH, Thompson JE: Splanchnicectomy for essen- sympathetic overactivity in the genesis of hypertension, this tial hypertension: Results in 1266 cases. JAMA 152: 1501– has recently again become a target for intervention. In a proof- 1504, 1953 of-principle study, Krum et al. (29) took up again the idea to 2. Morrissey DM, Brookes VS, Cooke WT: Sympathectomy in eliminate the function renal sympathetic nerves. In contrast to the treatment of hypertension: Review of 122 cases. Lancet the past nonselective surgical denervation riddled by numer- i: 403–408, 1953 ous adverse effects, the authors adopted percutaneous selective 3. Platt R, Stanbury SW: Sympathectomy in hypertension. Lancet i: 651–659, 1950 renal denervation to eliminate the afferent and efferent sympa- 4. Evelyn KA, Singh MM, Chapman WP, Perera GA, Thaler thetic nerves that conveniently lie within and immediately H: Effect of thoracolumbar sympathectomy on the clinical adjacent to the wall of the renal artery. To this end, a catheter course of primary (essential) hypertension: A ten-year connected to a radiofrequency generator was introduced into study of 100 sympathectomized patients compared with the lumen of the main renal artery. The study comprised 50 individually matched, symptomatically treated control patients at five Australian and European centers with expertise subjects. Am J Med 28: 188–221, 1960 in catheter-based interventions. For assessment of the efficacy 5. Esler M, Jennings G, Korner P, Willett I, Dudley F, Hasking of elimination of sympathetic denervation, renal noradrenaline G, Anderson W, Lambert G: Assessment of human sym- spillover was measured in a subgroup of patients, an elegant pathetic nervous system activity from measurements of indirect method to assess the activity of the sympathetic ner- norepinephrine turnover. Hypertension 11: 3–20, 1988 vous system (5). The spillover data documented substantial 6. DeQuattro V, Feng M: The sympathetic nervous system: The muse of primary hypertension. J Hum Hypertens afferent renal denervation in almost all patients. Renal angiog- 16[Suppl 1]: S64–S69, 2002 raphy as well as magnetic resonance angiography was per- 7. DiBona GF: Physiology in perspective: The wisdom of the formed early and late to exclude potential renovascular dam- body—Neural control of the kidney. Am J Physiol Regul age; renal artery aneurism or renal artery stenosis were not Integr Comp Physiol 289: R633–R641, 2005 observed. In such expert hands, only one major complica- 8. Campese VM, Kogosov E: Renal afferent denervation pre- tion—a renal artery dissection—occurred without long-term vents hypertension in rats with chronic renal failure. Hy- complications, but the safety in less expert hands awaits further pertension 25: 878–882, 1995 evaluation. 9. Campese VM: Neurogenic factors and hypertension in re- The effect on BP control was remarkable: Average office BP nal disease. Kidney Int Suppl 75: S2–S6, 2000 decreased progressively by 14 mmHg systolic and 10 mmHg 10. Schlaich MP, Socratous F, Hennebry S, Eikelis N, Lambert diastolic at month 1 and by 27 mmHg systolic and 17 mmHg EA, Straznicky N, Esler MD, Lambert GW: Sympathetic activation in chronic renal failure. J Am Soc Nephrol 20: diastolic at month 12, but not all patients showed a response. 933–939, 2009 One can even speculate that in the long run, interruption of 11. Converse RL Jr, Jacobsen TN, Toto RD, Jost CM, Cosentino sympathetic nerve traffic to and from the kidney may be ben- F, Fouad-Tarazi F, Victor RG: Sympathetic overactivity in eficial by BP-independent effects (e.g., reduction of left ventric- patients with chronic renal failure. N Engl J Med 327: 1912– ular hypertrophy) of insulin resistance and of vascular catas- 1918, 1992 trophes. The progressive decrease of BP is remarkable because 12. Ligtenberg G, Blankestijn PJ, Oey PL, Klein IH, Dijkhorst- of the theoretical possibility of regrowth of sympathetic nerves Oei LT, Boomsma F, Wieneke GH, van Huffelen AC, as documented after renal transplantation. Koomans HA: Reduction of sympathetic hyperactivity by It is still early to assess the potential clinical role of this enalapril in patients with chronic renal failure. N Engl innovative therapeutic approach and, as the authors indi- J Med 340: 1321–1328, 1999 cated, controlled prospective trials will be necessary. Several 13. Hausberg M, Kosch M, Harmelink P, Barenbrock M, Ho- aspects in the study are not ideal. Office BP is far from ideal hage H, Kisters K, Dietl KH, Rahn KH: Sympathetic nerve activity in end-stage renal disease. Circulation 106: 1974– for assessing BP, and 24-h BP measurements would have 1979, 2002 been preferable. This proof-of-principle study did not have a 14. Desir GV: Regulation of blood pressure and cardiovascular control group. Furthermore, given the efficacy of spironolac- function by renalase. Kidney Int 76: 366–370, 2009 tone and reduction of dietary salt intake in several studies of 15. Guyton AC, Coleman TG: Quantitative analysis of the resistant hypertension, it would have been desirable to as- pathophysiology of hypertension. 1969. J Am Soc Nephrol sess the efficacy of the novel procedure in patients who did 10: 2248–2258, 1999 not respond to such proven interventional procedures 16. Curtis JJ, Luke RG, Dustan HP, Kashgarian M, Whelchel 1888 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 4: 1886–1891, 2009

JD, Jones P, Diethelm AG: Remission of essential hyper- Klotho gene delivery prevents the tension after renal transplantation. N Engl J Med 309: 1009– progression of spontaneous hypertension 1015, 1983 and renal damage. Hypertension 54: 810–817, 17. Brantsma AH, Bakker SJ, de Zeeuw D, de Jong PE, Gan- sevoort RT: Urinary albumin excretion as a predictor of the 2009 development of hypertension in the general population. Wang Y, Tsun Z J Am Soc Nephrol 17: 331–335, 2006 In 1997, the klotho gene was identified and named after the 18. Keller G, Zimmer G, Mall G, Ritz E, Amann K: Nephron Greek goddess who spins the thread of life (1). Defective klotho number in patients with primary hypertension. N Engl gene expression in mice causes shortened lifespan, growth J Med 348: 101–108, 2003 retardation, hypogonadism, skin and muscle atrophy, vascular 19. Fava M, Dunner DL, Greist JH, Preskorn SH, Trivedi MH, Zajecka J, Cohen M: Efficacy and safety of mirtazapine in calcification, loss of bone mass, pulmonary emphysema, and major depressive disorder patients after SSRI treatment neural dysfunction, thus presenting an “aging phenotype” (2). failure: An open-label trial. J Clin Psychiatry 62: 413–420, The condition is associated with elevated concentrations of 2001 1,25-dihydroxyvitamin D3, of phosphate, and of calcium. The 20. DiBona GF: Sympathetic nervous system and the kidney in function of Klotho has been identified as a co-factor that in- hypertension. Curr Opin Nephrol Hypertens 11: 197–200, creases the affinity of the phosphaturic hormone fibroblast 2002 growth factor 23 (FGF-23) to some FGF receptors (3). One 21. Schlaich MP, Lambert E, Kaye DM, Krozowski Z, Camp- puzzling fact concerning the phosphaturic effect of FGF-23 is bell DJ, Lambert G, Hastings J, Aggarwal A, Esler MD: that control of phosphate excretion occurs in the proximal Sympathetic augmentation in hypertension: Role of nerve tubule, whereas the glycosidase klotho is expressed in the distal firing, norepinephrine reuptake, and angiotensin neuro- tubule (4). Thus, the interaction is potentially indirect. Klotho modulation. Hypertension 43: 169–175, 2004 can exert its effects in tissues or cells that do not express Klotho, 22. Esler M, Rumantir M, Kaye D, Jennings G, Hastings J, suggesting that it may function as an endocrine hormone (5). Socratous F, Lambert G: Sympathetic nerve biology in The serum phosphate concentration is of major importance essential hypertension. Clin Exp Pharmacol Physiol 28: 986– 989, 2001 for the cardiovascular risk not only in end-stage kidney disease 23. Barajas L, Muller J: The innervation of the juxtaglomerular but also in chronic kidney disease before the end stage, and apparatus and surrounding tubules: A quantitative analy- even phosphate concentrations within the normal range are sis by serial section electron microscopy. J Ultrastruct Res predictive of cardiovascular events in patients without kidney 43: 107–132, 1973 disease (6–8). These observations point to phosphate toxicity in 24. DiBona GF: The sympathetic nervous system and hyper- states of disruption of the bone–kidney–endocrine axis. tension: Recent developments. Hypertension 43: 147–150, It has been known for some time that the production of 2004 klotho is drastically reduced in human chronic renal failure, but 25. MacMahon S, Alderman MH, Lindholm LH, Liu L, decreased plasma levels of klotho have also been found in Sanchez RA, Seedat YK: Blood-pressure-related disease is a patients who were older than 40 yr (9,10). In this context, the global health priority. Lancet 371: 1480–1482, 2008 article by Wang and Sun (11) provides provocative information 26. Chapman N, Dobson J, Wilson S, Dahlo¨f B, Sever PS, concerning the effect of the antiaging hormone klotho on hy- Wedel H, Poulter NR, Anglo-Scandinavian Cardiac Out- pertension and renal damage. comes Trial Investigators: Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hy- It is known that overexpression of the klotho gene extends pertension 49: 839–845, 2007 the lifespan (12). Some of the downstream mechanisms poten- 27. Doumas M, Guo D, Papademetriou V: Carotid barorecep- tially relevant for life expectancy and cardiovascular risk had tor stimulation as a therapeutic target in hypertension and been identified, for instance effects on insulin/IGF-1 signaling, other cardiovascular conditions. Expert Opin Ther Targets increased nitric oxide availability, regulation of oxidative 13: 413–425, 2009 stress, and regulation of calcium channel activity (13). Of par- 28. Wustmann K, Kucera JP, Scheffers I, Mohaupt M, Kroon ticular interest for the cardiovascular and renal effects de- AA, de Leeuw PW, Schmidli J, Allemann Y, Delacre´taz E: scribed next is that klotho also protects against endothelial Effects of chronic baroreceptor stimulation on the auto- dysfunction (14). nomic cardiovascular regulation in patients with drug- The authors of this study administered adeno-associated vi- resistant arterial hypertension. Hypertension 54: 530–536, rus carrying mouse klotho full-length cDNA to spontaneously 2009 hypertensive rats (SHR) and matched Wistar Kyoto rats. The 29. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski readout of this study was changes in BP and production of J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, superoxide and NADPH oxidase activity (as indicators of oxi- Abraham WT, Esler M: Catheter-based renal sympathetic denervation for resistant hypertension: A multicenter dative stress) and NOX1, NOX2, and NOX4 in aorta and kid- safety and proof-of-principle cohort study. Lancet 373: ney. Furthermore, the morphology of the kidney was assessed 1275–1281, 2009 and plasma levels of the membrane and secreted forms of 30. Appel LJ: Another major role for dietary sodium reduction: klotho were measured. Improving blood pressure control in patients with resistant The results were remarkable. Whereas in untreated SHR BP hypertension. Hypertens 54: 444–446, 2009 increased progressively, the BP increase was abrogated in SHR Clin J Am Soc Nephrol 4: 1886–1891, 2009 Presse Re´nale 1889 that were treated with adenovirus and carried full-length One remarkable point is the observation that the vasculature klotho cDNA. The BP level did not decrease, however, to the did not express klotho, yet the vessels were affected by klotho level measured in WKY controls. gene delivery. Because gene delivery had increased plasma Plasma levels of the klotho isoforms (membrane and secreted klotho concentrations, klotho apparently acted as a hormone form) were significantly decreased in untreated SHR but in- (5). creased to the levels seen in WKY controls in the SHR that were This experimental study points to a novel aspect of the en- treated with adenovirus and carried full-length klotho cDNA. docrine bone–kidney–phosphate axis, namely BP and kidney In the kidney, klotho expression was decreased in untreated damage. The findings have no immediate consequences for SHR and was increased in the treated SHR. This was paralleled patient treatment, but watch out for further surprises from the by similar changes in urinary klotho. phosphate–FGF-23–klotho connection. In the SHR that were treated with adenovirus and carried References full-length klotho cDNA, the anti-inflammatory cytokine IL-10 1. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga was upregulated. IL-10 is known to ameliorate hypertensive T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume organ damage (15). E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI: Mutation of the mouse klotho gene leads to Evidence of oxidative stress was seen in the aorta and kidney a syndrome resembling ageing. Nature 390: 45–51, 1997 of untreated SHR (vascular superoxide production and 2. Kuro-o M: Klotho in chronic kidney disease: What’s new? NADPH oxidase activity), but this was reduced in treated rats. Nephrol Dial Transplant 24: 1705–1708, 2009 In the kidney, NOX2 expression was selectively upregulated 3. Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, in untreated SHR, and this was reverted by klotho gene deliv- Rosenblatt KP, Baum MG, Schiavi S, Hu MC, Moe OW, ery. There was no change in the expression of endothelial NO Kuro-o M: Regulation of fibroblast growth factor-23 sig- synthase. These findings were paralleled by changes in renal naling by klotho. J Biol Chem 281: 6120–6123, 2006 histology: Untreated SHR had atrophic cortical tubules with 4. Farrow EG, Davis SI, Summers LJ, White KE: Initial FGF23- dilation and proteinaceous material in the tubular lumen as mediated signaling occurs in the distal convoluted tubule. J Am Soc Nephrol 20: 955–960, 2009 well as glomerular collapse. These lesions were no longer seen 5. Wang Y, Sun Z: Current understanding of klotho. Ageing in SHR with klotho gene delivery. In parallel, the elevated Res Rev 8: 43–51, 2009 protein excretion in untreated rats was significantly decreased 6. Block GA, Hulbert-Shearon TE, Levin NW, Port FK: Asso- in the rats that treated with adenovirus and carried full-length ciation of serum phosphorus and calcium ϫ phosphate klotho cDNA. product with mortality risk in chronic hemodialysis pa- These findings raise several points. The prevention of the tients: a national study. Am J Kidney Dis 31: 607–617, 1998 progression of hypertension in this animal model of spontane- 7. Kestenbaum B, Sampson JN, Rudser KD, Patterson DJ, ous hypertension is remarkable, but the generalizability of this Seliger SL, Young B, Sherrard DJ, Andress DL: Serum observation to other forms of hypertension awaits further stud- phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol 16: 520–528, 2005 ies. The authors point to the remarkable parallelism that circu- 8. Tonelli M, Sacks F, Pfeffer M, Gao Z, Curhan G, Choles- lating Klotho decreases with age while conversely the preva- terol and Recurrent Events Trial Investigators: Relation lence of hypertension increases with age in humans (10,16). between serum phosphate level and cardiovascular event Further studies must show whether this is just association or is rate in people with coronary disease. Circulation 112: 2627– causal. 2633, 2005 The effect of klotho gene delivery was limited: It did prevent 9. Koh N, Fujimori T, Nishiguchi S, Tamori A, Shiomi S, the BP increase but failed to decrease the BP of SHR to the level Nakatani T, Sugimura K, Kishimoto T, Kinoshita S, Kuroki seen in WKY controls. Thus, the BP increase was aborted, but T, Nabeshima Y: Severely reduced production of klotho in the treatment had no antihypertensive effect. human chronic renal failure kidney. Biochem Biophys Res Commun 280: 1015–1020, 2001 It is known that vascular and renal superoxide production is 10. Xiao NM, Zhang YM, Zheng Q, Gu J: Klotho is a serum increased in SHR and plays a role in the pathogenesis of hy- factor related to human aging. Chin Med J (Engl) 117: 742– pertension (17). In view of the crucial role of the kidney for the 747, 2004 genesis of any form of hypertension, it is therefore of interest 11. Wang Y, Sun Z: Klotho gene delivery prevents the progres- that klotho reduced oxidative stress in the kidney with its sion of spontaneous hypertension and renal damage. Hy- presumed causal role in the genesis of hypertension (18). Fur- pertension 54: 810–817, 2009 thermore, the impressive effects on kidney morphology raise 12. Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, the issue to what extent klotho is involved in progression of Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, renal damage in general or whether the observed effect is Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, Kuro-o M: Suppression of aging in unique to BP-induced kidney damage. It is of note, however, mice by the hormone Klotho. Science 309: 1829–1833, 2005 that impressive amelioration of kidney damage was seen, al- 13. Yamamoto M, Clark JD, Pastor JV, Gurnani P, Nandi A, though the BP failed to be lowered to the level seen in the WKY Kurosu H, Miyoshi M, Ogawa Y, Castrillon DH, Rosenblatt controls. The kidney apparently is not only a major site of KP, Kuro-o M: Regulation of oxidative stress by the anti- klotho production (apart from the central nervous system) but aging hormone klotho. J Biol Chem 280: 38029–38034, 2005 also a target organ for klotho action. 14. Shimada T, Takeshita Y, Murohara T, Sasaki K, Egami K, 1890 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 4: 1886–1891, 2009

Shintani S, Katsuda Y, Ikeda H, Nabeshima Y, Imaizumi T: without expanding the extracellular fluid) but also can trigger Angiogenesis and vasculogenesis are impaired in the pre- lymphangiogenesis in the skin. A number of past experimental cocious-aging klotho mouse. Circulation 110: 1148–1155, studies had documented that salt loading caused BP-indepen- 2004 dent organ damage and inflammation (6,9,10). 15. Nonaka-Sarukawa M, Okada T, Ito T, Yamamoto K, This issue of BP-independent effects of salt has been given a Yoshioka T, Nomoto T, Hojo Y, Shimpo M, Urabe M, new twist by this study by Machnik et al.: The authors ampli- Mizukami H, Kume A, Ikeda U, Shimada K, Ozawa K: fied past observations of nonosmotic storage sodium in the skin Adeno-associated virus vector-mediated systemic inter- leukin-10 expression ameliorates hypertensive organ and documented added complexity. They now show that stor- damage in Dahl salt-sensitive rats. J Gene Med 10: 368– age of salt in the skin triggers lymphangiogenesis by a compli- 374, 2008 cated sequence of events and thus further impacts on BP. The 16. Ong KL, Cheung BM, Man YB, Lau CP, Lam KS: Preva- pointer in this direction was recent observations that macro- lence, awareness, treatment, and control of hypertension phages (i.e., the mononuclear phagocyte system) influence lym- among United States adults 1999–2004. Hypertension 49: phangiogenesis and that, in a malignancy model, hypertonicity 69–75, 2007 macrophage–produced factors triggered peritumoral lymph 17. Landmesser U, Cai H, Dikalov S, McCann L, Hwang J, Jo vessels (11,12). Furthermore, osmotic stress had been defined as H, Holland SM, Harrison DG: Role of p47(phox) in vascu- a critical feature of the lymphoid microenvironment (13). lar oxidative stress and hypertension caused by angioten- The authors tied all of these suggestions together and docu- sin II. Hypertension 40: 511–515, 2002 mented that hypertonicity of the interstitium as produced by 18. Guyton AC, Coleman TG: Quantitative analysis of the pathophysiology of hypertension. 1969. J Am Soc Nephrol feeding a high-salt diet provoked macrophage signaling, result- 10: 2248–2258, 1999 ing in the secretion of an isoform of vascular endothelial growth factor (VEGF), VEGF-C, a known factor that promotes Macrophages regulate salt-dependent lymphangiogenesis. The authors found stimulation of lymphangiogenesis in mice volume and blood pressure by a vascular fed a high-salt compared with a low-salt diet as documented by endothelial growth factor-C-dependent three-dimensional reconstruction of the lymph system. The buffering mechanisms. Nat Med 15: 545–552, causal role of macrophages for lymphangiogenesis was proved 2009 by the experiment that selective deletion of macrophages by Machnik A, Neuhofer W, Jantsch J, Dahlmann A, Tammela clodronate-containing liposomes prevented lymphangiogen- T, Machura K, Park JK, Beck FX, Mu¨ller DN, Derer W, esis: Clodronate-containing liposomes are taken up by macro- Goss J, Ziomber A, Dietsch P, Wagner H, van Rooijen N, phages but are toxic for them. Elimination of macrophages by Kurtz A, Hilgers KF, Alitalo K, Eckardt KU, Luft FC, clodronate-containing liposomes caused greater expansion of Kerjaschki D, Titze J the extracellular space and higher BP values. A classical concept about the relationship between salt (NaCl) These observations raised the issue of which signal is respon- and extracellular volume was that salt was retained as an sible for lymphangiogenesis. Promotion of lymphangiogenesis isosmotic fluid and that equilibration between sodium intake by macrophages was dependent on a molecule that has been and output was achieved after approximately 5 d (1). This view known to immunologists for quite some time as tonicity-re- has become problematic after disquieting deviations from the sponsive enhancer–binding protein (TonEBP) (13). Incubation prediction were found in astronauts who went into substan- of macrophages at high as compared with low NaCl concen- tially positive sodium balance without gaining weight, appar- trations increased the expression of TonEBP on the mRNA and ently storing salt without expanding the extracellular fluid protein level. TonEBP binds the promoter of the gene encoding space (2,3). This unexpected violation of past paradigms found VEGF-C, causing VEGF-C secretion by macrophages. The an explanation in the observation of Titze et al. (4) that sodium, causal role of VEGF-C secretion by macrophages was proved in addition to or instead of expanding the extracellular fluid by depleting or trapping VEGF by soluble VEGF-C receptor 3: space, may undergo ionic interaction with negatively charged Blocking VEGF-C signaling augmented interstitial hypertonic glycosaminoglycans (GAG) of the skin by binding directly as a volume retention and decreased endothelial nitric oxide syn- cation to the polysulfated negatively charged GAG GAG. This thase (eNOS) expression, causing major BP elevation in re- has important implications for salt-induced changes in body sponse to high-salt diet. So VEGF-C has been identified as the weight, tissue hydration, and BP regulation (5). These novel osmosensitive hypertonicity-driven gene involved in the gene- findings concerning the mechanism of sodium retention with- sis of salt-induced hypertension. ϩ out commensurate weight gain are irreconcilable with the clas- The issue that arises is whether this Na overload–triggered sical concept that sodium is retained primarily or exclusively by macrophage response via TonEBP and VEGF-C is injurious or is isosmotic expansion of the extracellular fluid. beneficial by counteracting the effect of high salt. The authors Salt does not only cause edema and hypertension but also showed that VEGF-C binds not only to the VEGF receptor BP-independent target organ damage (e.g., of heart and kidney) (VEGFR3) of lymphatic vessels but also to the endothelial (6–8). VEGFR2 receptor, activation of which upregulates the produc- The article discussed here now goes one step further and tion of vasodilatory NO. In other words, sodium overload, documents that salt not only can be stored nonosmotically (i.e., which tends to raise BP, also causes compensatory production Clin J Am Soc Nephrol 4: 1886–1891, 2009 Presse Re´nale 1891 of vasodilatory NO, which counteracts the pressure-inducing Long-term sodium balance in humans in a terrestrial space effect of salt. The efficacy of this compensatory mechanism is station simulation study. Am J Kidney Dis 40: 508–516, 2002 illustrated by the observation that eNOS knockout animals 3. Heer M, Baisch F, Kropp J, Gerzer R, Drummer C: High develop more severe hypertension upon salt loading (14). dietary sodium chloride consumption may not induce body fluid retention in humans. Am J Physiol Renal Physiol The sequence of events can be summarized as shown here: 278: F585–F595, 2000 3 ϩ 13 3 Na load interstitial Na TonEBP activated 4. Titze J, Shakibaei M, Schafflhuber M, Schulze-Tanzil G, 13 3 3 VEGF-C lymphangiogenesis drainage endothelial Porst M, Schwind KH, Dietsch P, Hilgers KF: Glycosami- cell eNOS13vasodilation noglycan polymerization may enable osmotically inactive The human relevance of this pathway is illustrated by the Naϩ storage in the skin. Am J Physiol Heart Circ Physiol 287: finding that in 25 patients with refractory hypertension—as H203–H208, 2004 ϩ compared with 15 control individuals—the plasma VEGF-C 5. Titze J: Water-free Na retention: Interaction with hyper- tension and tissue hydration. Blood Purif 26: 95–99, 2008 concentrations were significantly higher. 6. Matavelli LC, Zhou X, Varagic J, Susic D, Frohlich ED: Salt This study adds one further potential mechanism to the loading produces severe renal hemodynamic dysfunction genesis of high BP. The ramifications for hypertension in independent of arterial pressure in spontaneously hyper- chronic kidney disease are difficult to predict. It is an expres- tensive rats. Am J Physiol Heart Circ Physiol 292: H814– sion of the intelligence of nature that salt loading automatically H819, 2007 increases NO synthesis by endothelial cells to limit salt-induced 7. Ying WZ, Sanders PW: Dietary salt increases endothelial increase in BP, but the question that has to be addressed is nitric oxide synthase and TGF-beta1 in rat aortic endothe- whether this compensatory mechanism is disturbed in renal lium. Am J Physiol 277: H1293–H1298, 1999 8. Dworkin LD, Benstein JA, Tolbert E, Feiner HD: Salt re- failure and whether this is relevant for the particular salt sen- striction inhibits renal growth and stabilizes injury in rats sitivity of patients with chronic kidney disease. with established renal disease. J Am Soc Nephrol 7: 437–442, The storage of sodium without a commensurate increase in 1996 water must certainly caution against equating sodium retention 9. Frohlich ED: The salt conundrum: A hypothesis. Hyperten- with weight gain in dialysis patients; the aforementioned mech- sion 50: 161–166, 2007 anism would allow for sodium retention in the absence of 10. Sanders PW: Vascular consequences of dietary salt intake. weight gain—similar to what has been observed in astronauts Am J Physiol Renal Physiol 297: F237–F243, 2009 11. Kerjaschki D: The crucial role of macrophages in lym- (2). This has implications for the dry weight, which had origi- phangiogenesis. J Clin Invest 115: 2316–2319, 2005 nally been defined as the “body weight in the normotensive, 12. Schoppmann SF, Birner P, Stockl J, Kalt R, Ullrich R, nonedematous patient on dialysis”—the rationale to rely on Caucig C, Kriehuber E, Nagy K, Alitalo K, Kerjaschki D: weight alone deserves to be rethought. The storage of sodium Tumor-associated macrophages express lymphatic endo- may also be relevant to understanding the lag phenomenon thelial growth factors and are related to peritumoral lym- (i.e., the delayed decrease of BP in response to reduction of phangiogenesis. Am J Pathol 161: 947–956, 2002 extracellular volume) (15,16). Potentially prolonged elevation 13. Go WY, Liu X, Roti MA, Liu F, Ho SN: NFAT5/TonEBP of BP may reflect the delayed release of sodium certainly not mutant mice define osmotic stress as a critical feature of the lymphoid microenvironment. Proc Natl Acad Sci U S A 101: strictly related to the size of the extracellular space. 10673–10678, 2004 In retrospect, one can only admire the clinical acumen of 14. Leonard AM, Chafe LL, Montani JP, Van Vliet BN: In- Scribner et al. (17), who wrote in 1960, “As in the case of creased salt-sensitivity in endothelial nitric oxide synthase- nephrectomized dogs, hypertension appears to be influenced knockout mice. Am J Hypertens 19: 1264–1269, 2006 by the size of the extracellular space. The combination of di- 15. Ifudu O, Uribarri J, Rajwani I, Vlacich V, Reydel K, Delos- etary sodium restriction and ultrafiltration during dialysis per- reyes G, Friedman EA: Relation between interdialytic mits regulation of extracellular volume—although the explana- weight gain, body weight and nutrition in hemodialysis tion may no longer be perfectly correct, the practical patients. Am J Nephrol 22: 363–368, 2002 16. Charra B, Bergstrom J, Scribner BH: Blood pressure control consequences certainly are.” in dialysis patients: Importance of the lag phenomenon. References Am J Kidney Dis 32: 720–724, 1998 1. Welt LG: Clinical Disorders of Hydration and Acid-Base Equi- 17. Scribner BH, Buri R, Caner JE, Hegstrom R, Burnell JM: librium, Boston, Little, Brown and Company, 1955 The treatment of chronic uremia by means of intermittent 2. 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