User menu

Accès à distance ? S'identifier sur le proxy UCLouvain

PKD1 haploinsufficiency is associated with altered vascular reactivity and abnormal calcium signaling in the mouse aorta.

Primary tabs

Morel, Nicole [UCL] Vandenberg, Greet [UCL] Ahrabi, Ali [UCL] Caron, Nathalie [FUNDP] Desjardins, Fanny [UCL] Balligand, Jean-Luc [UCL] Devuyst, Olivier [UCL]

Mutations in PKD1 are associated with autosomal dominant polycystic kidney disease (ADPKD), which leads to major cardiovascular complications. We used mice with a heterozygous deletion of Pkd1 (Pkd1 ( +/- )) and wild-type (Pkd1 ( +/+ )) littermates to test whether Pkd1 haploinsufficiency is associated with a vascular phenotype in different age groups. Systolic blood pressure measured by the tail-cuff method was similar up to 20 weeks of age, but significantly higher in 30-week-old Pkd1 ( +/- ) compared to Pkd1 (+/+). By contrast, similar telemetric recordings were obtained in unrestrained Pkd1 (+/-) and Pkd1 (+/+) mice. The contractile responses evoked by KCl or phenylephrine were similar in young animals but increased in abdominal aortas of 30-week-old Pkd1 (+/-) mice, and acetylcholine-evoked relaxation was depressed. Basal cytosolic calcium, KCl, and phenylephrine-evoked calcium signals were significantly lower in the Pkd1 (+/-) aortas, whereas calcium release evoked by caffeine or thapsigargin was significantly larger. These changes were paralleled with a significant change in the mRNA expression of Pkd2, Trpc1, Orai1, and Serca2a in the aortas from Pkd1 (+/-) vs. Pkd1 (+/+). These results are the first to indicate that haploinsufficiency in Pkd1 is associated with altered intracellular calcium homeostasis and increased vascular reactivity in the aorta with compensatory changes in transport proteins involved in the calcium signaling network.

Document type Article de périodique (Journal article) – Journal Article, Research Support, Non-U.S. Gov't
Access type Accès restreint
Publication date 2009
Language Anglais
Journal information "Pflügers Archiv - European journal of physiology" - Vol. 457, no. 4, p. 845-856 (2009)
Peer reviewed yes
Publisher Springer ((Germany) Berlin)
issn 0031-6768
Publication status Publié
Affiliations UCL - MD/MINT - Département de médecine interne
UCL - (SLuc) Service de néphrologie
MESH Subject Transcription, Genetic ; TRPP Cation Channels - genetics - metabolism ; Polycystic Kidney, Autosomal Dominant - genetics - physiopathology ; Phenylephrine - pharmacology ; Muscle, Smooth, Vascular - metabolism ; Muscle Tonus - drug effects - physiology ; Mice ; Male ; Kidney - physiology ; Humans ; Hemodynamics ; Gene Dosage ; Endothelium - physiology - physiopathology ; Cholinergic Agents - pharmacology ; Calcium Signaling - physiology ; Calcium - metabolism ; Aorta - anatomy & histology - drug effects - physiology ; Animals ; Aging - physiology ; Adrenergic alpha-Agonists - pharmacology ; Acetylcholine - pharmacology
Links
  1. Ahrabi AK, Terryn S, Valenti G, Caron N, Serradeil-Le Gal C, Raufaste D, Nielsen S, Horie S, Verbavatz JM, Devuyst O (2007) PKD1 Haploinsufficiency causes a syndrome of inappropriate antidiuresis in mice. J Am Soc Nephrol 18:1740–1753
  2. Beech D. J., Muraki K., Flemming R., Non-selective cationic channels of smooth muscle and the mammalian homologues ofDrosophilaTRP : Smooth muscle TRPs and cationic channels, 10.1113/jphysiol.2004.068734
  3. Boulter C, Mulroy S, Webb S, Fleming S, Brindle K, Sandford R (2001) Cardiovascular, skeletal, and renal defects in mice with a targeted disruption of the Pkd1 gene. Proc Natl Acad Sci U S A 98:12174–12179
  4. Brueggemann LI, Markun DR, Henderson KK, Cribbs LL, Byron KL (2006) Pharmacological and electrophysiological characterization of store-operated currents and capacitative Ca(2+) entry in vascular smooth muscle cells. J Pharmacol Exp Ther 317:488–499
  5. Ecder T, Schrier RW (2001) Hypertension in autosomal-dominant polycystic kidney disease: early occurrence and unique aspects. J Am Soc Nephrol 12:194–200
  6. Eggermont J A, Wuytack F, Verbist J, Casteels R, Expression of endoplasmic-reticulum Ca2+-pump isoforms and of phospholamban in pig smooth-muscle tissues, 10.1042/bj2710649
  7. Ghisdal P, Gomez JP, Morel N (2000) Action of a NO donor on the excitation-contraction pathway activated by noradrenaline in rat superior mesenteric artery. J Physiol 522:83–96
  8. Ghisdal P, Vandenberg G, Morel N (2003) Rho-dependent kinase is involved in agonist-activated calcium entry in rat arteries. J Physiol 551:855–867
  9. Griffin MD, Torres VE, Grande JP, Kumar R (1997) Vascular expression of polycystin. J Am Soc Nephrol 8:616–626
  10. Hanaoka K, Qian F, Boletta A, Bhunia AK, Piontek K, Tsiokas L, Sukhatme VP, Guggino WB, Germino GG (2000) Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents. Nature 408:990–994
  11. Henrion D, Laher I, Laporte R, Bevan JA (1992) Angiotensin II amplifies arterial contractile response to norepinephrine without increasing Ca++ influx: role of protein kinase C. J Pharmacol Exp Ther 261:835–40
  12. Hilfiker-Kleiner D, Kaminski K, Podewski E, Bonda T, Schaefer A, Sliwa K, Forster O, Quint A, Landmesser U, Doerries C, Luchtefeld M, Poli V, Schneider MD, Balligand JL, Desjardins F, Ansari A, Struman I, Nguyen NQ, Zschemisch NH, Klein G, Heusch G, Schulz R, Hilfiker A, Drexler H (2007) A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 128:589–600
  13. Inoue R., Okada T., Onoue H., Hara Y., Shimizu S., Naitoh S., Ito Y., Mori Y., The Transient Receptor Potential Protein Homologue TRP6 Is the Essential Component of Vascular  1-Adrenoceptor-Activated Ca2+-Permeable Cation Channel, 10.1161/01.res.88.3.325
  14. Kanno Y, Okada H, Moriwaki K, Nagao S, Takahashi H, Suzuki H (2002) The effects of antihypertensive agents on the survival rate of polycystic kidney disease in Han:SPRD rats. Hypertens Res 25:939–943
  15. Kim K, Drummond I, Ibraghimov-Beskrovnaya O, Klinger K, Arnaout MA (2000) Polycystin 1 is required for the structural integrity of blood vessels. Proc Natl Acad Sci U S A 97:1731–1736
  16. Kip SN, Hunter LW, Ren Q, Harris PC, Somlo S, Torres VE, Sieck GC, Qian Q (2005) [Ca2+]i reduction increases cellular proliferation and apoptosis in vascular smooth muscle cells: relevance to the ADPKD phenotype. Circ Res 96:873–880
  17. Koulen P, Cai Y, Geng L, Maeda Y, Nishimura S, Witzgall R, Ehrlich BE, Somlo S (2002) Polycystin-2 is an intracellular calcium release channel. Nat Cell Biol 4:191–197
  18. Krenek P, Morel N, Kyselovic J, Wibo M (2004) Amlodipine at high dose increases preproendothelin-1 expression in the ventricles and aorta of normotensive rats. J Hypertens 22:827–835
  19. Kurtz TW, Griffin KA, Bidani AK, Davisson RL, Hall JE (2005) Recommendations for blood pressure measurement in animals: summary of an AHA scientific statement from the Council on High Blood Pressure Research, Professional and Public Education Subcommittee. Arterioscler Thromb Vasc Biol 25:478–479
  20. Lipskaia L, del Monte F, Capiod T, Yacoubi S, Hadri L, Hours M, Hajjar RJ, Lompre AM (2005) Sarco/endoplasmic reticulum Ca2+-ATPase gene transfer reduces vascular smooth muscle cell proliferation and neointima formation in the rat. Circ Res 97:488–95
  21. Lu W, Fan X, Basora N, Babakhanlou H, Law T, Rifai N, Harris PC, Perez-Atayde AR, Rennke HG, Zhou J (1999) Late onset of renal and hepatic cysts in Pkd1-targeted heterozygotes. Nat Genet 21:160–161
  22. Luo Y, Vassilev PM, Li X, Kawanabe Y, Zhou J (2003) Native polycystin 2 functions as a plasma membrane Ca2+-permeable cation channel in renal epithelia. Mol Cell Biol 23:2600–2607
  23. Muto S, Aiba A, Saito Y, Nakao K, Nakamura K, Tomita K, Kitamura T, Kurabayashi M, Nagai R, Higashihara E, Harris PC, Katsuki M, Horie S (2002) Pioglitazone improves the phenotype and molecular defects of a targeted Pkd1 mutant. Hum Mol Genet 11:1731–1742
  24. Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AE, Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J (2003) Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 33:129–137
  25. Patton C, Thompson S, Epel D (2004) Some precautions in using chelators to buffer metals in biological solutions. Cell Calcium 35:427–431
  26. Peel SE, Liu B, Hall IP (2008) ORAI and store-operated calcium influx in human airway smooth muscle cells. Am J Respir Cell Mol Biol 38:744–749
  27. Pelat M, Dessy C, Massion P, Desager JP, Feron O, Balligand JL (2003) Rosuvastatin decreases caveolin-1 and improves nitric oxide-dependent heart rate and blood pressure variability in apolipoprotein E−/− mice in vivo. Circulation 107:2480–2486
  28. Persu A, Stoenoiu MS, Messiaen T, Davila S, Robino C, El-Khattabi O, Mourad M, Horie S, Feron O, Balligand JL, Wattiez R, Pirson Y, Chauveau D, Lens XM, Devuyst O (2002) Modifier effect of ENOS in autosomal dominant polycystic kidney disease. Hum Mol Genet 11:229–241
  29. Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:e45
  30. Pirson Y, Chauveau D, Devuyst O (2005) Autosomal dominant polycystic kidney disease. In: Davisson AM et al (ed) Oxford textbook of clinical nephrology. 3rd edn. Oxford University Press, Oxford, pp 2304–2324
  31. Qian F, Germino FJ, Cai Y, Zhang X, Somlo S, Germino GG (1997) PKD1 interacts with PKD2 through a probable coiled-coil domain. Nat Genet 16:179–183
  32. Qian Q, Hunter LW, Du H, Ren Q, Han Y, Sieck GC (2007) Pkd2+/− vascular smooth muscles develop exaggerated vasocontraction in response to phenylephrine stimulation. J Am Soc Nephrol 18:485–493
  33. Qian Q, Hunter LW, Li M, Marin-Padilla M, Prakash YS, Somlo S, Harris PC, Torres VE, Sieck GC (2003) Pkd2 haploinsufficiency alters intracellular calcium regulation in vascular smooth muscle cells. Hum Mol Genet 12:1875–1880
  34. Qian Q, Li M, Cai Y, Ward CJ, Somlo S, Harris PC, Torres VE (2003) Analysis of the polycystins in aortic vascular smooth muscle cells. J Am Soc Nephrol 14:2280–2287
  35. Tai K, Hamaide MC, Debaix H, Gailly P, Wibo M, Morel M (2008) Agonist-evoked calcium entry in vascular smooth muscle cells requires IP3 receptor-mediated activation of TRPC1. Eur J Pharmacol 583:135–147
  36. Taylor CW, Laude AJ (2002) IP3 receptors and their regulation by calmodulin and cytosolic Ca2+. Cell Calcium 32:321–334
  37. Torres VE, Harris PC (2006) Mechanisms of disease: autosomal dominant and recessive polycystic kidney diseases. Nat Clin Pract Nephrol 2:40–55 (quiz 55)
  38. Torres VE, Harris PC, Pirson Y (2007) Autosomal dominant polycystic kidney disease. Lancet 369:1287–1301
  39. Tsiokas L, Arnould T, Zhu C, Kim E, Walz G, Sukhatme VP (1999) Specific association of the gene product of PKD2 with the TRPC1 channel. Proc Natl Acad Sci U S A 96:3934–3939
  40. Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3:RESEARCH0034
  41. Wang D, Iversen J, Strandgaard S (1999) Contractility and endothelium-dependent relaxation of resistance vessels in polycystic kidney disease rats. J Vasc Res 36:502–509
  42. Wang D, Iversen J, Wilcox CS, Strandgaard S (2003) Endothelial dysfunction and reduced nitric oxide in resistance arteries in autosomal-dominant polycystic kidney disease. Kidney Int 64:1381–1388
  43. Wu G, Markowitz GS, Li L, D’Agati VD, Factor SM, Geng L, Tibara S, Tuchman J, Cai Y, Park JH, van Adelsberg J, Hou H Jr., Kucherlapati R, Edelmann W, Somlo S (2000) Cardiac defects and renal failure in mice with targeted mutations in Pkd2. Nat Genet 24:75–78
Bibliographic reference Morel, Nicole ; Vandenberg, Greet ; Ahrabi, Ali ; Caron, Nathalie ; Desjardins, Fanny ; et. al. PKD1 haploinsufficiency is associated with altered vascular reactivity and abnormal calcium signaling in the mouse aorta.. In: Pflügers Archiv - European journal of physiology, Vol. 457, no. 4, p. 845-856 (2009)
Permanent URL http://hdl.handle.net/2078.1/14154