SFB 699:  Structural, Physiological and Molecular Determinants of Kidney Function

• Subject Area: Medicine ; Biology
• Term: from 2006 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 14945784

• Final Report Year: 2018

Final Report Abstract

Major aims of the SFB699 were the investigation of structure-function relationships of glomeruli, tubuli, interstitial cells and reno-endocrine cells. Major achievements were the development of the nephrocyte model from Drosophila and the application of 2 photon-in vivo microscopy for the functional study of mouse podocytes. These investigations revealed a transcellular protein transport within podocytes which may be of clinical relevance. Within the tubular system the functions of CFTR, anoctamins, NKCC2 isoforms and inwardly rectifying potassium channels were characterized. The molecular mechanisms underlying hereditary tubular transport defects were identified. The influence of systemic inflammation (sepsis) on specific tubular transport processes was characterized. A major success was the recent structural analysis of the polycystin 2 ion channel, mutations of which lead to polycystic kidney disease. Of major clinical impact is also the analysis of cells contributing to progressive renal fibrosis. It could be shown that about 50% of cells contributing to renal fibrosis originate outside the kidney, immigrate into the diseased kidney and transform into fibrotic cells. Moreover, first evidence for a central role of resident interstitial fibroblasts for repair of damaged tubular cells was obtained by 2photon in vivo microscopy. Novel informations also with clinical relevance were also obtained for renin producing cells, which are the essential regulators of the renin-angiotensin-aldosterone system. Major findings in this context were the functional roles of connexins and of angiotensin II receptors in renin cells.

Publications

• A truncated polycystin-2 protein causes polycystic kidney disease and retinal degeneration in transgenic rats. J Am Soc Nephrol. 2006 Oct;17(10):2719-30
  Gallagher AR, Hoffmann S, Brown N, Cedzich A, Meruvu S, Podlich D, Feng Y, Könecke V, de Vries U, Hammes HP, Gretz N, Witzgall R
  (See online at https://doi.org/10.1681/asn.2005090979)
• Macula densa control of renin secretion and preglomerular resistance in mice with selective deletion of the B isoform of the Na,K,2Cl co-transporter. J Am Soc Nephrol. 2006 Aug;17(8):2143-52
  Oppermann M, Mizel D, Huang G, Li C, Deng C, Theilig F, Bachmann S, Briggs J, Schnermann J, Castrop H
  (See online at https://doi.org/10.1681/asn.2006040384)
• The calcium paradoxon of renin release: calcium suppresses renin exocytosis by inhibition of calcium-dependent adenylate cyclases AC5 and AC6. Circ Res. 2006 Nov 24;99(11):1197-206
  Grünberger C, Obermayer B, Klar J, Kurtz A, Schweda F
  (See online at https://doi.org/10.1161/01.res.0000251057.35537.d3)
• Connexin40 is essential for the pressure control of renin synthesis and secretion. Circ Res. 2007 Mar 2;100(4):556-63
  Wagner C, de Wit C, Kurtz L, Grünberger C, Kurtz A, Schweda F
  (See online at https://doi.org/10.1161/01.res.0000258856.19922.45)
• Lack of connexin 40 causes displacement of renin-producing cells from afferent arterioles to the extraglomerular mesangium. J Am Soc Nephrol. 2007 Apr;18(4):1103-11
  Kurtz L, Schweda F, de Wit C, Kriz W, Witzgall R, Warth R, Sauter A, Kurtz A, Wagner C
  (See online at https://doi.org/10.1681/asn.2006090953)
• Peroxisome proliferator-activated receptor-gamma is involved in the control of renin gene expression. Hypertension. 2007 Nov;50(5):939-44
  Todorov VT, Desch M, Schmitt-Nilson N, Todorova A, Kurtz A
  (See online at https://doi.org/10.1161/hypertensionaha.107.092817)
• Pituitary adenylate cyclase-activating polypeptide stimulates renin secretion via activation of PAC1 receptors. J Am Soc Nephrol. 2007 Apr;18(4):1150-6
  Hautmann M, Friis UG, Desch M, Todorov V, Castrop H, Segerer F, Otto C, Schütz G, Schweda F
  (See online at https://doi.org/10.1681/asn.2006060633)
• Regulation of renal sodium transporters during severe inflammation. J Am Soc Nephrol. 2007 Apr;18(4):1072-83
  Schmidt C, Höcherl K, Schweda F, Kurtz A, Bucher M
  (See online at https://doi.org/10.1681/asn.2006050454)
• Renal function in mice with targeted disruption of the A isoform of the Na-K-2Cl co-transporter. J Am Soc Nephrol. 2007 Feb;18(2):440-8
  Oppermann M, Mizel D, Kim SM, Chen L, Faulhaber-Walter R, Huang Y, Li C, Deng C, Briggs J, Schnermann J, Castrop H
  (See online at https://doi.org/10.1681/asn.2006091070)
• The podocyte-specific inactivation of Lmx1b, Ldb1 and E2a yields new insight into a transcriptional network in podocytes. Dev Biol. 2007 Apr 15;304(2):701-12
  Suleiman H, Heudobler D, Raschta AS, Zhao Y, Zhao Q, Hertting I, Vitzthum H, Moeller MJ, Holzman LB, Rachel R, Johnson R, Westphal H, Rascle A, Witzgall R
  (See online at https://doi.org/10.1016/j.ydbio.2007.01.020)
• Development of renin expression in the mouse kidney. Kidney Int. 2008 Jan;73(1):43-51
  Sauter A, Machura K, Neubauer B, Kurtz A, Wagner C
  (See online at https://doi.org/10.1038/sj.ki.5002571)
• Bestrophin 1 promotes epithelial-to-mesenchymal transition of renal collecting duct cells. J Am Soc Nephrol. 2009 Jul;20(7):1556-64
  Aldehni F, Spitzner M, Martins JR, Barro-Soria R, Schreiber R, Kunzelmann K
  (See online at https://doi.org/10.1681/asn.2008090987)
• CD4+ T cells control the differentiation of Gr1+ monocytes into fibrocytes. Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17892-7
  Niedermeier M, Reich B, Rodriguez Gomez M, Denzel A, Schmidbauer K, Göbel N, Talke Y, Schweda F, Mack M
  (See online at https://doi.org/10.1073/pnas.0906070106)
• Connexin expression in renin-producing cells. J Am Soc Nephrol. 2009 Mar;20(3):506-12
  Kurtz L, Janssen-Bienhold U, Kurtz A, Wagner C
  (See online at https://doi.org/10.1681/asn.2008030252)
• Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations. N Engl J Med. 2009 May 7;360(19):1960-70
  Bockenhauer D, Feather S, Stanescu HC, Bandulik S, Zdebik AA, Reichold M, Tobin J, Lieberer E, Sterner C, Landoure G, Arora R, Sirimanna T, Thompson D, Cross JH, van't Hoff W, Al Masri O, Tullus K, Yeung S, Anikster Y, Klootwijk E, Hubank M, Dillon MJ, Heitzmann D, Arcos-Burgos M, Knepper MA, Dobbie A, Gahl WA, Warth R, Sheridan E, Kleta R
  (See online at https://doi.org/10.1056/nejmoa0810276)
• Loss of TMEM16A causes a defect in epithelial Ca2+-dependent chloride transport. J Biol Chem. 2009 Oct 16;284(42):28698-703
  Ousingsawat J, Martins JR, Schreiber R, Rock JR, Harfe BD, Kunzelmann K
  (See online at https://doi.org/10.1074/jbc.m109.012120)
• Substitution of connexin40 with connexin45 prevents hyperreninemia and attenuates hypertension. Kidney Int. 2009 Mar;75(5):482-9
  Schweda F, Kurtz L, de Wit C, Janssen-Bienhold U, Kurtz A, Wagner C
  (See online at https://doi.org/10.1038/ki.2008.637)
• Atrap deficiency increases arterial blood pressure and plasma volume. J Am Soc Nephrol. 2010 Mar;21(3):468-77
  Oppermann M, Gess B, Schweda F, Castrop H
  (See online at https://doi.org/10.1681/asn.2009060658)
• KCNJ10 gene mutations causing EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function. Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14490-5
  Reichold M, Zdebik AA, Lieberer E, Rapedius M, Schmidt K, Bandulik S, Sterner C, Tegtmeier I, Penton D, Baukrowitz T, Hulton SA, Witzgall R, Ben-Zeev B, Howie AJ, Kleta R, Bockenhauer D, Warth R
  (See online at https://doi.org/10.1073/pnas.1003072107)
• Physiology of kidney renin. Physiol Rev. 2010 Apr;90(2):607-73
  Castrop H, Höcherl K, Kurtz A, Schweda F, Todorov V, Wagner C
  (See online at https://doi.org/10.1152/physrev.00011.2009)
• Selective deletion of Connexin 40 in renin-producing cells impairs renal baroreceptor function and is associated with arterial hypertension. Kidney Int. 2010 Oct;78(8):762-8
  Wagner C, Jobs A, Schweda F, Kurtz L, Kurt B, Lopez ML, Gomez RA, van Veen TA, de Wit C, Kurtz A
  (See online at https://doi.org/10.1038/ki.2010.257)
• Calmodulin-dependent activation of the epithelial calcium-dependent chloride channel TMEM16A. FASEB J. 2011 Mar;25(3):1058-68
  Tian Y, Kongsuphol P, Hug M, Ousingsawat J, Witzgall R, Schreiber R, Kunzelmann K
  (See online at https://doi.org/10.1096/fj.10-166884)
• Polycystin-2 takes different routes to the somatic and ciliary plasma membrane. J Cell Biol. 2011 Feb 21;192(4):631-45
  Hoffmeister H, Babinger K, Gürster S, Cedzich A, Meese C, Schadendorf K, Osten L, de Vries U, Rascle A, Witzgall R
  (See online at https://doi.org/10.1083/jcb.201007050)
• Stimulation of renin secretion by catecholamines is dependent on adenylyl cyclases 5 and 6. Hypertension. 2011 Mar;57(3):460-8
  Aldehni F, Tang T, Madsen K, Plattner M, Schreiber A, Friis UG, Hammond HK, Han PL, Schweda F
  (See online at https://doi.org/10.1161/hypertensionaha.110.167130)
• The connexin 40 A96S mutation causes renin-dependent hypertension. J Am Soc Nephrol. 2011 Jun;22(6):1031-40
  Lübkemeier I, Machura K, Kurtz L, Neubauer B, Dobrowolski R, Schweda F, Wagner C, Willecke K, Kurtz A
  (See online at https://doi.org/10.1681/asn.2010101047)
• Acute endotoxemia in mice induces downregulation of megalin and cubilin in the kidney. Kidney Int. 2012 Jul;82(1):53-9
  Schreiber A, Theilig F, Schweda F, Höcherl K
  (See online at https://doi.org/10.1038/ki.2012.62)
• Task3 potassium channel gene invalidation causes low renin and salt-sensitive arterial hypertension. Endocrinology. 2012 Oct;153(10):4740-8
  Penton D, Bandulik S, Schweda F, Haubs S, Tauber P, Reichold M, Cong LD, El Wakil A, Budde T, Lesage F, Lalli E, Zennaro MC, Warth R, Barhanin J
  (See online at https://doi.org/10.1210/en.2012-1527)
• Transcutaneous measurement of renal function in conscious mice. Am J Physiol Renal Physiol. 2012 Sep;303(5):F783-8
  Schreiber A, Shulhevich Y, Geraci S, Hesser J, Stsepankou D, Neudecker S, Koenig S, Heinrich R, Hoecklin F, Pill J, Friedemann J, Schweda F, Gretz N, Schock-Kusch D
  (See online at https://doi.org/10.1152/ajprenal.00279.2012)
• Deletion of von Hippel-Lindau protein converts renin-producing cells into erythropoietin-producing cells. J Am Soc Nephrol. 2013 Feb;24(3):433-44
  Kurt B, Paliege A, Willam C, Schwarzensteiner I, Schucht K, Neymeyer H, Sequeira-Lopez ML, Bachmann S, Gomez RA, Eckardt KU, Kurtz A
  (See online at https://doi.org/10.1681/asn.2012080791)
• High-content siRNA screen reveals global ENaC regulators and potential cystic fibrosis therapy targets. Cell. 2013 Sep 12;154(6):1390-400
  Almaça J, Faria D, Sousa M, Uliyakina I, Conrad C, Sirianant L, Clarke LA, Martins JP, Santos M, Heriché JK, Huber W, Schreiber R, Pepperkok R, Kunzelmann K, Amaral MD
  (See online at https://doi.org/10.1016/j.cell.2013.08.045)
• LMX1B is essential for the maintenance of differentiated podocytes in adult kidneys. J Am Soc Nephrol. 2013 Nov;24(11):1830-48
  Burghardt T, Kastner J, Suleiman H, Rivera-Milla E, Stepanova N, Lottaz C, Kubitza M, Böger CA, Schmidt S, Gorski M, de Vries U, Schmidt H, Hertting I, Kopp J, Rascle A, Moser M, Heid IM, Warth R, Spang R, Wegener J, Mierke CT, Englert C, Witzgall R
  (See online at https://doi.org/10.1681/asn.2012080788)
• Anoctamin 1 induces calcium-activated chloride secretion and proliferation of renal cyst-forming epithelial cells. Kidney Int. 2014 May;85(5):1058-67
  Buchholz B, Faria D, Schley G, Schreiber R, Eckardt KU, Kunzelmann K
  (See online at https://doi.org/10.1038/ki.2013.418)
• Hypoxia-inducible factor-1α causes renal cyst expansion through calcium-activated chloride secretion. J Am Soc Nephrol. 2014 Mar;25(3):465-74
  Buchholz B, Schley G, Faria D, Kroening S, Willam C, Schreiber R, Klanke B, Burzlaff N, Jantsch J, Kunzelmann K, Eckardt KU
  (See online at https://doi.org/10.1681/asn.2013030209)
• Mistargeting of peroxisomal EHHADH and inherited renal Fanconi's syndrome. N Engl J Med. 2014 Jan 9;370(2):129-38
  Klootwijk ED, Reichold M, Helip-Wooley A, Tolaymat A, Broeker C, Robinette SL, Reinders J, Peindl D, Renner K, Eberhart K, Assmann N, Oefner PJ, Dettmer K, Sterner C, Schroeder J, Zorger N, Witzgall R, Reinhold SW, Stanescu HC, Bockenhauer D, Jaureguiberry G, Courtneidge H, Hall AM, Wijeyesekera AD, Holmes E, Nicholson JK, O'Brien K, Bernardini I, Krasnewich DM, Arcos-Burgos M, Izumi Y, Nonoguchi H, Jia Y, Reddy JK, Ilyas M, Unwin RJ, Gahl WA, Warth R, Kleta R
  (See online at https://doi.org/10.1056/nejmoa1307581)
• The calcium-activated chloride channel Anoctamin 1 contributes to the regulation of renal function. Kidney Int. 2014 Jun;85(6):1369-81
  Faria D, Rock JR, Romao AM, Schweda F, Bandulik S, Witzgall R, Schlatter E, Heitzmann D, Pavenstädt H, Herrmann E, Kunzelmann K, Schreiber R
  (See online at https://doi.org/10.1038/ki.2013.535)
• Intravital Imaging Reveals Angiotensin II-Induced Transcytosis of Albumin by Podocytes. J Am Soc Nephrol. 2016 Mar;27(3):731-44
  Schießl IM, Hammer A, Kattler V, Gess B, Theilig F, Witzgall R, Castrop H
  (See online at https://doi.org/10.1681/asn.2014111125)
• Molecular insights into lipid-assisted Ca(2+) regulation of the TRP channel Polycystin-2. Nat Struct Mol Biol. 2017 Feb;24(2):123-130
  Wilkes M, Madej MG, Kreuter L, Rhinow D, Heinz V, De Sanctis S, Ruppel S, Richter RM, Joos F, Grieben M, Pike AC, Huiskonen JT, Carpenter EP, Kühlbrandt W, Witzgall R, Ziegler C
  (See online at https://doi.org/10.1038/nsmb.3357)
• Natriuretic Peptide Receptor Guanylyl Cyclase-A in Podocytes is Renoprotective but Dispensable for Physiologic Renal Function. J Am Soc Nephrol. 2017 Jan;28(1):260-277
  Staffel J, Valletta D, Federlein A, Ehm K, Volkmann R, Füchsl AM, Witzgall R, Kuhn M, Schweda F
  (See online at https://doi.org/10.1681/asn.2015070731)