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now clearly established, subsequent trials should directly compare other new thera- see original article on page 1121 peutic agents with tacrolimus, or system- atically evaluate the addition of a second A defect in vasopressin secretion agent to maintain remission and abbreviate the duration of tacrolimus therapy. In addi- in autosomal dominant tion, subsequent prospective trials of pedi- atric SRNS should specifically stratify polycystic kidney disease patients according to histopathology and potential biomarkers, 13 and also perform Daniel G. Bichet 1 targeted genotyping for all currently recog- nized genetic causes of SRNS. Such an A nephrogenic defect in urine concentration is well established in approach will enable the development of a patients with polycystic kidney disease, but Ho et al. report a defect in more personalized and eff ective therapeutic the increase of plasma vasopressin in response to dehydration. strategy for this vexing disease. On a cellular level, transient receptor potential channels responsible for DISCLOSURE osmoperception could interact with TRPPs encoded by the polycystic The authors declared no competing interests. PKD1 and PKD2. REFERENCES Kidney International (2012) 82, 1051 – 1053. doi: 10.1038/ki.2012.271 1 . Hogg R , Middleton J , Vehaskari VM . Focal segmental glomerulosclerosis: epidemiology aspects in children and adults. Pediatr Nephrol 2007 ; 22 : 183 – 186 . 1 2 . MacHardy N , Miles PV , Massengill SF et al. Manage- Ho et al., in this issue of Kidney Interna- volume estimated by ultrasound. Measure- ment patterns of childhood-onset nephrotic tional, demonstrate that autosomal domi- ment of maximal urine osmolality aft er syndrome. Pediatr Nephrol 2009 ; 4 : 2193 – 2201 . 3 . Faul C , Donnelly M , Merscher-Gomez S et al. nant polycystic kidney disease (ADPKD) an overnight dehydration was then pro- The actin cytoskeleton of kidney podocytes is is associated not only with lower urinary posed as an inexpensive way to screen for a direct target of the antiproteinuric effect of osmolality but also with less vasopressin ADPKD as compared with the more costly cyclosporine A. Nat Med 2008 ; 14 : 931 – 938 . 3 4 . Roberti I , Vyas S . Long-term outcome of children with secretion. As PKD expression has renal ultrasound. steroid-resistant nephrotic syndrome treated with been found in hypothalamic nuclei, these tacrolimus. Pediatr Nephrol 2010 ; 25 : 1117 – 1124 . clinical observations suggest a specifi c role The new fi ndings of Ho et al.: defective 5 . Choudhry S , Bagga A , Hari P et al. Efficacy and safety of tacrolimus versus cyclosporine of PKD genes in osmoregulation. vasopressin release in patients with in children with steroid-resistant nephrotic ADPKD syndrome: a randomized controlled trial. In the study by Ho et al. , 1 adults and Am J Kidney Dis 2009 ; 53 : 760 – 769 . A defect in renal concentrating 6 . Butani L , Ramsamooj R . Experience with tacrolimus capacity is well demonstrated in children with ADPKD were matched in children with steroid-resistant nephrotic polycystic kidney disease with unaff ected family members and syndrome . Pediatr Nephrol 2009 ; 24: 1517 – 1523 . 2 7 . Rennert WP , Kala UK , Jacobs D et al. Pulse Martinez-Maldonado et al. published as demonstrated higher plasma osmolality cyclophosphamide for steroid-resistant focal early as 1972 that the inability to concentrate and lower urinary osmolality (710 ver- segmental glomerulosclerosis. Pediatr Nephrol urine was a common fi nding both in chro- sus 920 mosmol / kg H O) in response to 1999 ; 13 : 113 – 116 . 2 8 . Bajpai A , Bagga A , Hari P et al. Intravenous nic kidney disease and in polycystic kidney dehy dration. Plasma vasopressin levels cyclophosphamide in steroid-resistant nephrotic disease (PKD). However, the urinary con- remained unchanged in adult ADPKD syndrome. Pediatr Nephrol 2003 ; 18 : 351 – 356 . centration defect was observed in ADPKD patients, contrasting with increased val- 9 . Plank C , Kalb V , Hinkes B et al. Cyclosporin A 3 is superior to cyclophosphamide in children patients with normal renal function and ues in controls. Th ese vasopressin levels with steroid-resistant nephrotic syndrome: was probably related to physical alterations are critical, as patients with hereditary or a randomized controlled multicentre trial of the renal medulla by cysts originating in acquired nephrogenic diabetes insipidus by the Arbeitsgemeinschaft fü r Pä diatrische Nephrologie . Pediatr Nephrol 2008 ; 23 : 1483 – 1493 . the collecting duct, principally the cortico- always have higher plasma vasopressin 10 . Gulati A , Sinha A , Gupta A et al. Treatment with medullary junction. In these early studies, values. 4 tacrolimus and prednisolone is preferable to an inverse correlation was demonstrated intravenous cyclophosphamide as the initial therapy for children with steroid-resistant nephrotic between urinary osmolality and renal Expression of PKD1 and PKD2 genes syndrome . Kidney Int 2012 ; 82: 1130–1135 . in the Allen Mouse and Human Brain 11 . The primary nephrotic syndrome in children . Identi- fication of patients with minimal change nephrotic Atlases syndrome from initial response to prednisone. A 1Department of Physiology and Medicine, Hô pital Th e Allen Institute for Brain Science, report of the International Study of Kidney Disease du Sacr é -Coeur, Universit é de Montr é al , Montr é al , established in 2003 by Paul Allen (one of in Children . J Pediatr 1981 ; 98: 561 – 564 . Canada 12 . Gipson DS , Trachtman H , Kaskel FJ et al. Clinical trial the original founders of Microsoft ), set out Correspondence: Daniel G. Bichet, Department of focal segmental glomerulosclerosis in children to describe the expression of all known of Physiology and Medicine, H ô pital du and young adults. Kidney Int 2011 ; 80 : 868 – 878 . genes in the adult mouse brain, 5,6 and 13 . Wei C , El Hindi S , Li J et al. Circulating urokinase Sacr é -Coeur, Universit é de Montr é al, 5400 West receptor as a cause of focal segmental Gouin Boulevard, Montr é al, Qu é bec, Canada colorimetric in situ hybridization data for glomerulosclerosis. Nat Med 2011 ; 17 : 952 – 960 . H4J 1C5. E-mail: [email protected] 21,000 genes are now posted online with

Kidney International (2012) 82 1051 commentary

Hypertonic form a mechanical and thermosensitive + molecular sensor. Heteromeric mem- 12 + + brane receptors and membrane chan- nels, inclu ding transient receptor potential 13 –55 mV VP channels, are an active area of research. Antidiuresis Th e diversity of function and regula- + + TRPP2 TRPV4 tion obtained through heteromeric inter- + actions is potentially large; for example, an -4 / transient receptor potential TRPV4 TRPP2 Set vanilloid 4 (AQP4 / TRPV4) complex has point Set –60 mV Basal been found to be essential for volume con- VP point trol in .14 + + TRPV1 expressed centrally in supra- optic and paraventricular magnocellular Diuresis cells or TRPV4 expressed in peripheral portal neurons sensing portal vein osmo- lality could form heteromeric units with –65 mV VP TRPP2 (PKD2) and decrease vasopressin Hypotonic production when PKD1 or PKD2 is mutated (remember that TRPP2 forms Figure 1 | Osmoreception in hypothalamic vasopressin neurons. Changes in osmolality cause a functional complex with TRPP1). inversely proportional changes in soma volume. Shrinkage activates nonselective cation channels (NSCCs), and the ensuing depolarization increases action potential firing rate and vasopressin (VP) release from axon terminals in the neurohypophysis. Increased vasopressin levels in blood enhance Regulation of vasopressin by tonicity water reabsorption by the kidney (antidiuresis) to restore extracellular fluid osmolality toward the information relayed by central set point. Hypotonic stimuli inhibit NSCCs. The resulting hyperpolarization and inhibition of firing osmoreceptor neurons expressing reduce vasopressin release and promote diuresis. The lack of osmotic stimulation of vasopressin observed in the polycystic kidney disease patients described by Ho et al. 1 might be attributable TRPV1 and peripheral osmoreceptor to heteromeric NSCC/ TRPP2 channels. In the figure, the NSCCs are represented at the surface of neurons expressing TRPV4 magnocellular cells producing vasopressin with positive ions Ca + + and Na + entering the cells. As summarized elegantly by Bourque, 8 They could form heteromers with mutated TRPP2 in PKD patients and result in less vasopressin early studies provided clear evidence produced for the same osmotic stimulus. Heteromeric TRPV4/ TRPP2 could also exist in peripheral neurons acting as tonoreceptors in the portal vein (not schematized here) (adapted from ref. 23). that ‘ cellular dehydration’ (that is, cell shrinking) was required for thirst and vasopressin release to be stimulated during extracellular fl uid hyperosmola- open access. Ho et al. 1 determined that Possible interactions between lity: these responses could be induced by the transcripts of Avp (the gene coding for polycystin-1, polycystin-2, and infusions of concentrated solutions con- vasopressin) as well as Pkd1 and Pkd2 were TRPV proteins responsible for taining membrane-impermeable solutes, clearly enriched in paraventricular, supra- osmoregulation which extract water from cells, but not chiasmatic, and supraoptic hypothalamic Polycystin-1 (encoded by PKD1 , the gene by infusions of solutes that readily equili- nuclei known to produce vasopressin. Th e responsible for polycystic kidney disease brate across the cell membrane (such resolution of the Allen Brain Atlas is ‘ quasi- type 1) and polycystin-2 (PKD2 ) are ex- as urea). Verney coined the term ‘ osmo- cellular ’ : it is not possible to deter mine pressed in the kidney and are responsible receptor’ to designate the specialized colocalization in the same vasopressin- for ADPKD: TRPP2 (PKD2) is a six- sensory elements. He further showed that producing magnocellular cells, but fi gures transmembrane-domain protein that may these were present in the brain and pos- from the article of Ho et al., 1 are convinc- form a Ca + + permeable cation channel in tulated that they might comprise ‘ tiny ing. As Koester and Insel 7 have commented, association with TRPP1 (polycystin-1, or osmometers ’ and ‘ stretch receptors ’ that it will be important in future Allen Institute PKD1). TRPP1 and TRPP2 are members would allow osmotic stimuli to be ‘ trans- for Brain Science initiatives to combine of the large family of transient receptor muted into electrical’ signals.15 Osmore- microarray analysis with electrophysiology8 potential channels (reviewed by Nilius 9 ). ceptors are therefore defi ned functional- and neurotransmitter immunochemistry to In addition to renal epithelial cells, poly- ly as neurons endowed with an intrinsic describe the exact interactions between cystins are also abundantly expressed in ability to detect changes in extracellular PKD1/ 2 and TRPVs (transient receptor the myocytes of the blood vessels, where fl uid tonicity, and it is now known that potential vanilloid-type) in magnocellular they may have a role in pressure sensing.10 both cerebral ( Figure 1 ) and peripheral cells producing vasopressin or in other osmo- Kottgen et al.11 used transfected MDCK or osmoreceptors16 contribute to the body regulatory neurons of the subfornical organ, HEK 293 cells to demonstrate that TRPP2 fl uid balance. the organum vasculosum of the lamina ter- (polycystin-2) engages in a heteromeric The cellular basis for osmoreceptor minalis, and the median preoptic nucleus.8 interaction with the TRPV4 channel to potentials has been characterized by patch-

1052 Kidney International (2012) 82 commentary

clamp recordings and morphometric anal- tute most of the cysts in ADPKD. When with central and nephrogenic defects in osmo- − / − regulation . Kidney Int 2012 ; 82 : 1121–1129 . ysis in magnocellular cells isolated from PCK rats and Brattleboro ( Avp ) rats 2 . Martinez-Maldonado M , Yium JJ , Eknoyan G et al. the supraoptic nucleus of the adult rat. In (rats with autosomal recessive central dia- Adult polycystic kidney disease: studies of the defect these cells, stretch-inactivating cationic betes insipidus) were crossed, a complete in urine concentration . Kidney Int 1972 ; 2 : 107 – 113 . 3 . Gabow PA , Kaehny WD , Johnson AM et al. The clinical channels transduce osmotically evoked inhibition of cystogenesis was observed utility of renal concentrating capacity in polycystic − / − changes in cell volume into functionally in PCK Avp rats, demonstrating that kidney disease . Kidney Int 1989 ; 35: 675 – 680 . relevant changes in membrane potential. vasopressin directly regulates cyst growth 4 . Babey M , Kopp P , Robertson GL . Familial forms of 18 diabetes insipidus: clinical and molecular charac- Magnocellular neurons also operate as in PKD. Also, in a recent study in teristics . Nat Rev Endocrinol 2011 ; 7 : 701 – 714 . intrinsic Na + detectors. Th e N-terminal which 63 ADPKD subjects were ran- 5 . Jones AR , Overly CC , Sunkin SM . The Allen Brain variant of the transient receptor potential domly matched 1:2 to historical controls Atlas: 5 years and beyond. Nat Rev Neurosci 2009 ; 10 : 821 – 828 . channel (TRPV1) is an osmotically acti- by sex, hypertension, age, and baseline to- 6 . Jessberger S , Gage FH . ZOOMING IN: a new high- vated channel expressed in magnocellular tal kidney volume (assessed by magnetic resolution gene expression atlas of the brain. cells that produce vasopressin and in the resonance imaging) and thrice-annual Mol Syst Biol [online] 2007 ; 3 : 75 . 7 . Koester SE , Insel TR . Mouse maps of gene expression circumventricular organs, the organum estimated glomerular fi ltration rate, ADP- in the brain. Genome Biol [online] 2007 ; 8 : 212 . vasculosum of the lamina terminalis, and KD cyst growth progressed more slowly 8 . Bourque CW . Central mechanisms of the subfornical organ. 8 Since osmoregula- with tolvaptan, a non-peptide vasopressin osmosensation and systemic osmoregulation . − / − Nat Rev Neurosci 2008 ; 9 : 519 – 531 . tion still operates in Trpv1 mice, other V2 receptor antagonist, than in historical 9 . Nilius B . Polycystins under pressure. Cell 2009 ; 139 : osmosensitive neurons or pathways must controls. 19 It is not known whether less 466 – 467 . be able to compensate for loss of central vasopressin is produced in response to 10 . Sharif-Naeini R , Folgering JH , Bichet D et al. Polycystin-1 and -2 dosage regulates pressure osmoreceptor function. Aff erent neurons vasopressin V2 receptor antagonism in sensing . Cell 2009 ; 139 : 587 – 596 . expressing the osmotically activated ion ADPKD patients as compared with nor- 11 . Kottgen M , Buchholz B , Garcia-Gonzalez MA et al. channel TRPV4 in the thoracic dorsal root mal subjects. Elevated intracellular cyclic TRPP2 and TRPV4 form a polymodal sensory channel complex . J Cell Biol 2008 ; 182 : 437 – 447 . ganglia that innervate hepatic blood vessels adenosine monophosphate, in response 12 . Kern A , Albarran-Zeckler R , Walsh HE et al. A p o - and detect physiological hypo-osmotic to vasopressin, occurs in some forms of ghrelin receptor forms heteromers with DRD2 in shift s in blood osmolality have recently PKD and is known to contribute to cyst hypothalamic neurons and is essential for anorexigenic effects of DRD2 agonism. 16 been identified. In mice lacking the formation, in part by stimulating prolifer- Neuron 2012 ; 73 : 317 – 332 . osmotically activated TRPV4, ative activity of cyst epithelial cells.18,20,21 13 . Cheng W , Yang F , Takanishi CL et al. Thermosensitive TRPV channel subunits coassemble into heteromeric hepatic sensory neurons no longer exhibit Also, apical mislocalization of vasopressin channels with intermediate conductance and osmosensitive inward currents, and activa- type 2 receptor to the apical membrane in gating properties . J Gen Physiol 2007 ; 129 : 191 – 207 . tion of peripheral osmoreceptors in vivo PKD collecting duct cells could increase 14 . Benfenati V , Caprini M , Dovizio M et al. A n aquaporin-4/transient receptor potential vanilloid is abolished. In a large cohort of human salt and water transport through aqua- 4 (AQP4/TRPV4) complex is essential for cell- recipients of liver transplants, who presum- -2 water channels and epithelial volume control in astrocytes. Proc Natl Acad Sci ably have denervated livers, plasma osmo- sodium channels expressed in the same USA 2011 ; 108 : 2563 – 2568 . 22 15 . Verney E . The antidiuretic hormone and the factors lality is signifi cantly elevated compared cells. Whether such apical vasopressin which determine its release. Proc R Soc London B with that in healthy controls, suggesting type 2 receptor localization contributes to Biol Sci 1947 ; 135 : 2 5– 2 6. the presence of an inhibitory vasopressin enhanced fl uid retention and hyperten- 16 . Lechner SG , Markworth S , Poole K et al. T h e molecular and cellular identity of peripheral eff ect of hyponatremia, perceived in the sion in PKD remains to be determined. osmoreceptors. Neuron 2011 ; 69 : 332 – 344 . 16 portal vein from hepatic afferents. In summary, there is defective vaso- 17 . Ciura S , Liedtke W , Bourque CW . Hypertonicity TRPV1 (expressed in central neurons) and pressin production in response to dehy- sensing in organum vasculosum lamina terminalis neurons: a mechanical process involving TRPV1 TRPV4 (expressed in peripheral neurons) dration in PKD patients that may be but not TRPV4 . J Neurosci 2011 ; 31 : 14669 – 14676 . thus appear to play entirely comple mentary explained by a direct interaction between 1 8 . W a n g X , W u Y , W a r d C J et al. Vasopressin directly roles in osmoreception. Note that TRPV4 TRPP and TRPV channels. Th is observa- regulates cyst growth in polycystic kidney disease. J Am Soc Nephrol 2008 ; 19 : 102 – 108 . expression seems to be more important tion might be clinically applied to increase 19 . Higashihara E , Torres VE , Chapman AB et al. peripherally than centrally, since hyper- urine fl ow in PKD patients and potentially Tolvaptan in autosomal dominant polycystic tonicity sensing in the organum vasculo- retard cyst formation. kidney disease: three years’ experience. Clin J Am Soc Nephrol 2011 ; 6 : 2499 – 2507 . sum of the lamina terminalis is a 20 . Belibi FA , Reif G , Wallace DP et al. Cyclic AMP DISCLOSURE mecha nical process involving TRPV1 but promotes growth and secretion in human polycystic DGB has received honoraria from Otsuka not TRPV4. 17 kidney epithelial cells. Kidney Int 2004 ; 66 : 964 – 973 . Pharmaceuticals and PepsiCo; grant / research 21 . Gattone 2nd VH , Wang X , Harris PC et al. support from Otsuka Pharmaceuticals; and Inhibition of renal cystic disease development A defect in vasopressin secretion in paid expenses from Otsuka Pharmaceu- and progression by a vasopressin V2 receptor ticals and PepsiCo. He has consulted for antagonist. Nat Med 2003 ; 9 : 1323 – 1326 . response to dehydration might be Otsuka Pharmaceuticals and PepsiCo and is 22 . Saigusa T , Reichert R , Guare J et al. Collecting benefi cial to ADPKD patients a member of the Speakers Bureau for Otsuka duct cells that lack normal cilia have mislocalized Approximately 600,000 people in the Pharmaceuticals. vasopressin-2 receptors . Am J Physiol Renal Physiol United States have ADPKD, and vaso- 2012 ; 302 : F801 – F808 . REFERENCES 23 . Prager-Khoutorsky M , Bourque CW . Osmosensation pressin is a potent activator of adenylyl 1 . Ho T , Godefroid N , Gruzon D et al. Autosomal in vasopressin neurons: changing actin density to cyclase in collecting duct cells that consti- dominant polycystic kidney disease is associated optimize function. Trends Neurosci 2010 ; 33: 7 6– 8 3.

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