Top

Published in:

01-07-2011 | Educational Review

TRPC channel modulation in podocytes—inching toward novel treatments for glomerular disease

Authors: Shafic El Hindi, Jochen Reiser

Published in: Pediatric Nephrology | Issue 7/2011

Abstract

Glomerular kidney disease is a major healthcare burden and considered to represent a sum of disorders that evade a refined and effective treatment. Excellent biological and genetic studies have defined pathways that go awry in podocytes, which are the regulatory cells of the glomerular filter. The question now is how to define targets for novel improved therapies. In this review, we summarize critical points around targeting the TRPC6 channel in podocytes.

Available only for authorised users

Hogg RJ, Portman RJ, Milliner D, Lemley KV, Eddy A, Ingelfinger J (2000) Evaluation and management of proteinuria and nephrotic syndrome in children: recommendations from a pediatric nephrology panel established at the National Kidney Foundation conference on proteinuria, albuminuria, risk, assessment, detection, and elimination (PARADE). Pediatrics 105(6):1242–1249PubMedCrossRef

Reiser J, Gupta V, Kistler AD (2010) Toward the development of podocyte-specific drugs. Kidney Int 77(8):662–628PubMedPubMedCentralCrossRef

Möller CC, Flesche J, Reiser J (2009) Sensitizing the slit diaphragm with TRPC6 ion channels. J Am Soc Nephrol 20(5):950–953PubMedCrossRef

Reiser J, Polu KR, Möller CC, Kenlan P, Altintas MM, Wei C, Faul C, Herbert S, Villegas I, Avila-Casado C, McGee M, Sugimoto H, Brown D, Kalluri R, Mundel P, Smith PL, Clapham DE, Pollak MR (2005) TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet 37(7):739–744PubMedPubMedCentralCrossRef

Faul C, Asanuma K, Yanagida-Asanuma E, Kim K, Mundel P (2007) Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton. Trends Cell Biol 17(9):428–437PubMedCrossRef

Rodewald R, Karnovsky MJ (1974) Porous substructure of the glomerular slit diaphragm in the rat and mouse. J Cell Biol 60(2):423–433PubMedPubMedCentralCrossRef

Reiser J, Kriz W, Kretzler M, Mundel P (2000) The glomerular slit diaphragm is a modified adherens junction. J Am Soc Nephrol 11(1):1–8PubMedCrossRef

Wartiovaara J, Ofverstedt LG, Khoshnoodi J, Zhang J, Mäkelä E, Sandin S, Ruotsalainen V, Cheng RH, Jalanko H, Skoglund U, Tryggvason K (2004) Nephrin strands contribute to a porous slit diaphragm scaffold as revealed by electron tomography. J Clin Invest 14(10):1475–1483CrossRef

Tryggvason K, Wartiovaara J (2001) Molecular basis of glomerular permselectivity. Curr Opin Nephrol Hypertens 10(4):543–549PubMedCrossRef

10.

Ruotsalainen V, Ljungberg P, Wartiovaara J, Lenkkeri U, Kestilä M, Jalanko H, Holmberg C, Tryggvason K (1999) Nephrin is specifically located at the slit diaphragm of glomerular podocytes. Proc Natl Acad Sci USA 96(14):7962–7967PubMedCrossRefPubMedCentral

11.

Rantanen M, Palmén T, Pätäri A, Ahola H, Lehtonen S, Aström E, Floss T, Vauti F, Wurst W, Ruiz P, Kerjaschki D, Holthöfer H (2002) Nephrin TRAP mice lack slit diaphragms and show fibrotic glomeruli and cystic tubular lesions. J Am Soc Nephrol 13(6):1586–1594PubMedCrossRef

12.

Chuang PY, He JC (2009) Signaling in regulation of podocyte phenotypes. Nephron Physiol 111(2):9–15CrossRef

13.

Clapham DE (2003) TRP channels as cellular sensors. Nature 426(6966):517–524PubMedCrossRef

14.

Venkatachalam K, Montell C (2007) TRP channels. Annu Rev Biochem 76:387–417PubMedPubMedCentralCrossRef

15.

Eid SR, Cortright DN (2009) Transient receptor potential channels on sensory nerves. Handb Exp Pharmacol 194:261–281CrossRef

16.

Kiselyov K, Xu X, Kuo TH, Mozhayeva G, Pessah I, Mignery G, Zhu X, Birnbaumer L, Muallem S (1998) Functional interaction between InsP3 receptors and store-operated Htrp3 channels. Nature 396(6710):478–482PubMedCrossRef

17.

Kiselyov K, Mignery GA, Zhu MX, Muallem S (1999) The N-terminal domain of the IP3 receptor gates store-operated hTrp3 channels. Mol Cell 4(3):423–429PubMedCrossRef

18.

Zhu MX (2005) Multiple roles of calmodulin and other Ca(2+)-binding proteins in the functional regulation of TRP channels. Pflugers Arch 451(1):105–115PubMedCrossRef

19.

Hofmann T, Schaefer M, Schultz G, Gudermann T (2002) Subunit composition of mammalian transient receptor potential channels in living cells. Proc Natl Acad Sci USA 99(11):7461–7466PubMedCrossRefPubMedCentral

20.

Dryer SE, Reiser J (2010) TRPC6 channels and their binding partners in podocytes: role in glomerular filtration and pathophysiology. Am J Physiol Renal Physiol 299(4):F689–F701PubMedPubMedCentralCrossRef

21.

Winn MP, Conlon PJ, Lynn KL, Farrington MK, Creazzo T, Hawkins AF, Daskalakis N, Kwan SY, Ebersviller S, Burchette JL, Pericak-Vance MA, Howell DN, Vance JM, Rosenberg PB (2005) A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science 308(5729):1801–1804PubMedCrossRef

22.

Kestilä M, Lenkkeri U, Männikkö M, Lamerdin J, McCready P, Putaala H, Ruotsalainen V, Morita T, Nissinen M, Herva R, Kashtan CE, Peltonen L, Holmberg C, Olsen A, Tryggvason K (1998) Positionally cloned gene for a novel glomerular protein–nephrin–is mutated in congenital nephrotic syndrome. Mol Cell 11(4):575–582CrossRef

23.

Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, Dahan K, Gubler MC, Niaudet P, Antignac C (2000) NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 24(4):349–354PubMedCrossRef

24.

Niaudet P, Gubler MC (2006) WT1 and glomerular diseases. Pediatr Nephrol 21(11):1653–1660CrossRefPubMed

25.

Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ, Mathis BJ, Rodríguez-Pérez JC, Allen PG, Beggs AH, Pollak MR (2000) Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet 24(3):251–256PubMedCrossRef

26.

Schaefer M (2005) Homo- and heteromeric assembly of TRP channel subunits. Pflugers Arch 451(1):35–42PubMedCrossRef

27.

Dietrich A, Chubanov V, Kalwa H, Rost BR, Gudermann T (2006) Cation channels of the transient receptor potential superfamily: their role in physiological and pathophysiological processes of smooth muscle cells. Pharmacol Ther 112(3):744–760PubMedCrossRef

28.

Shih NY, Li J, Karpitskii V, Nguyen A, Dustin ML, Kanagawa O, Miner JH, Shaw AS (1999) Congenital nephrotic syndrome in mice lacking CD2-associated protein. Science 286(5438):312–315PubMedCrossRef

29.

Grunkemeyer JA, Kwoh C, Huber TB, Shaw AS (2005) CD2-associated protein (CD2AP) expression in podocytes rescues lethality of CD2AP deficiency. J Biol Chem 280(33):29677–29681PubMedCrossRef

30.

Schindl R, Romanin C (2007) Assembly domains in TRP channels. Biochem Soc Trans 5(Pt 1):84–85CrossRef

31.

Estacion M, Li S, Sinkins WG, Gosling M, Bahra P, Poll C, Westwick J, Schilling WP (2004) Activation of human TRPC6 channels by receptor stimulation. J Biol Chem 279(21):22047–22056PubMedCrossRef

32.

Gudermann T, Hofmann T, Mederos y Schnitzler M, Dietrich A (2004) Activation, subunit composition and physiological relevance of DAG-sensitive TRPC proteins. Novartis Found Symp 258:103–118, discussion 118–122, 155–159, 263–266PubMed

33.

Wedel BJ, Vazquez G, McKay RR, Bird GStJ, Putney JW Jr (2003) A calmodulin/inositol 1,4,5-trisphosphate (IP3) receptor-binding region targets TRPC3 to the plasma membrane in a calmodulin/IP3 receptor-independent process. J Biol Chem 278(28):25758–25765PubMedCrossRef

34.

Smyth JT, Lemonnier L, Vazquez G, Bird GS, Putney JW Jr (2006) Dissociation of regulated trafficking of TRPC3 channels to the plasma membrane from their activation by phospholipase C. J Biol Chem 281(17):11712–11720PubMedCrossRef

35.

Cayouette S, Lussier MP, Mathieu EL, Bousquet SM, Boulay G (2004) Exocytotic insertion of TRPC6 channel into the plasma membrane upon Gq protein-coupled receptor activation. J Biol Chem 279(8):7241–7246PubMedCrossRef

36.

Heeringa SF, Möller CC, Du J, Yue L, Hinkes B, Chernin G, Vlangos CN, Hoyer PF, Reiser J, Hildebrandt F (2009) A novel TRPC6 mutation that causes childhood FSGS. PLoS One 4(11):e7771PubMedPubMedCentralCrossRef

37.

Lepage PK, Lussier MP, Barajas-Martinez H, Bousquet SM, Blanchard AP, Francoeur N, Dumaine R, Boulay G (2006) Identification of two domains involved in the assembly of transient receptor potential canonical channels. J Biol Chem 281(41):30356–30364PubMedCrossRef

38.

Hinkes BG, Mucha B, Vlangos CN, Gbadegesin R, Liu J, Hasselbacher K, Hangan D, Ozaltin F, Zenker M, Hildebrandt F, Arbeitsgemeinschaft für Paediatrische Nephrologie Study Group (2007) Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2). Pediatrics 119(4):e907–e919PubMedCrossRef

39.

Möller CC, Wei C, Altintas MM, Li J, Greka A, Ohse T, Pippin JW, Rastaldi MP, Wawersik S, Schiavi S, Henger A, Kretzler M, Shankland SJ, Reiser J (2007) Induction of TRPC6 channel in acquired forms of proteinuric kidney disease. J Am Soc Nephrol 18(1):29–36PubMedCrossRef

40.

Ronco P, Debiec H (2006) New insights into the pathogenesis of membranous glomerulonephritis. Curr Opin Nephrol Hypertens 15(3):258–263PubMedCrossRef

41.

Glassock RJ (2004) The treatment of idiopathic membranous nephropathy: a dilemma or a conundrum? Am J Kidney Dis 44(3):562–566PubMedCrossRef

42.

Beck LH Jr, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, Klein JB, Salant DJ (2009) M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 361(1):11–21PubMedPubMedCentralCrossRef

43.

Imai H, Hamai K, Komatsuda A, Ohtani H, Miura AB (1997) IgG subclasses in patients with membranoproliferative glomerulonephritis, membranous nephropathy, and lupus nephritis. Kidney Int 51(1):270–276PubMedCrossRef

44.

Pippin JW, Durvasula R, Petermann A, Hiromura K, Couser WG, Shankland SJ (2003) DNA damage is a novel response to sublytic complement C5b-9-induced injury in podocytes. J Clin Invest 111(6):877–885PubMedPubMedCentralCrossRef

45.

Cybulsky AV, Bonventre JV, Quigg RJ, Lieberthal W, Salant DJ (1990) Cytosolic calcium and protein kinase C reduce complement-mediated glomerular epithelial injury. Kidney Int 38(5):803–811PubMedCrossRef

46.

Topham PS, Haydar SA, Kuphal R, Lightfoot JD, Salant DJ (1999) Complement-mediated injury reversibly disrupts glomerular epithelial cell actin microfilaments and focal adhesions. Kidney Int 55(5):1763–1775PubMedCrossRef

47.

Brooks RC, McCarthy KD, Lapetina EG, Morell P (1989) Receptor-stimulated phospholipase A2 activation is coupled to influx of external calcium and not to mobilization of intracellular calcium in C62B glioma cells. J Biol Chem 264(33):20147–20153PubMedCrossRef

48.

Wenzel RR (2005) Renal protection in hypertensive patients: selection of antihypertensive therapy. Drugs 65[Suppl 2]:29–39PubMedCrossRef

49.

Alaniz C, Brosius FC 3rd, Palmieri J (1993) Pharmacologic management of adult idiopathic nephrotic syndrome. Clin Pharm 12(6):429–439PubMed

50.

Hauser PV, Pippin JW, Kaiser C, Krofft RD, Brinkkoetter PT, Hudkins KL, Kerjaschki D, Reiser J, Alpers CE, Shankland SJ (2010) Novel siRNA delivery system to target podocytes in vivo. PLoS One 5(3):e9463PubMedPubMedCentralCrossRef

51.

Chiang WC, Geel TM, Altintas MM, Sever S, Ruiters MH, Reiser J (2010) Establishment of protein delivery systems targeting podocytes. PLoS One 5(7):e11837PubMedPubMedCentralCrossRef

52.

Hartleben B, Gödel M, Meyer-Schwesinger C, Liu S, Ulrich T, Köbler S, Wiech T, Grahammer F, Arnold SJ, Lindenmeyer MT, Cohen CD, Pavenstädt H, Kerjaschki D, Mizushima N, Shaw AS, Walz G, Huber TB (2010) Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J Clin Invest 120(4):1084–1096PubMedPubMedCentralCrossRef

53.

Schlöndorff J, Del Camino D, Carrasquillo R, Lacey V, Pollak MR (2009) TRPC6 mutations associated with focal segmental glomerulosclerosis cause constitutive activation of NFAT-dependent transcription. Am J Physiol Cell Physiol 296(3):C558–C569PubMedPubMedCentralCrossRef

Title: TRPC channel modulation in podocytes—inching toward novel treatments for glomerular disease
Authors: Shafic El Hindi
Jochen Reiser
Publication date: 01-07-2011
Publisher: Springer Berlin Heidelberg
Published in: Pediatric Nephrology / Issue 7/2011
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-010-1718-4

Keynote webinar | Spotlight on medication adherence

Springer Medicine

TRPC channel modulation in podocytes—inching toward novel treatments for glomerular disease

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 7/2011

Assessment of long-term renal complications in extremely low birth weight children

Ciliopathies: an expanding disease spectrum

Pathogenesis and therapy of focal segmental glomerulosclerosis: an update

Clinical outcomes in children with Henoch–Schönlein purpura nephritis grade IIIa or IIIb

Solutions for peritoneal dialysis in children: recommendations by the European Pediatric Dialysis Working Group

An unusual case of hyperkalaemia in infancy: question