Skip to main content
Top
Published in: Pediatric Nephrology 4/2014

Open Access 01-04-2014 | Review

Megabladder mouse model of congenital obstructive nephropathy: genetic etiology and renal adaptation

Author: Kirk M. McHugh

Published in: Pediatric Nephrology | Issue 4/2014

Login to get access

Abstract

Congenital obstructive nephropathy remains one of the leading causes of chronic renal failure in children. The direct link between obstructed urine flow and abnormal renal development and subsequent dysfunction represents a central paradigm of urogenital pathogenesis that has far-reaching clinical implications. Even so, a number of diagnostic, prognostic, and therapeutic quandaries still exist in the management of congenital obstructive nephropathy. Studies in our laboratory have characterized a unique mutant mouse line that develops in utero megabladder, variable hydronephrosis, and progressive renal failure. Megabladder mice represent a valuable functional model for the study of congenital obstructive nephropathy. Recent studies have begun to shed light on the genetic etiology of mgb −/− mice as well as the molecular pathways controlling disease progression in these animals.
Literature
1.
go back to reference Singh S, Robinson M, Nahi F, Coley B, Robinson M, Bates C, Kornacker K, McHugh KM (2007) Identification of a unique transgenic mouse line that develops megabladder, obstructive uropathy, and renal dysfunction. J Am Soc Nephrol 18:461–471PubMedCrossRef Singh S, Robinson M, Nahi F, Coley B, Robinson M, Bates C, Kornacker K, McHugh KM (2007) Identification of a unique transgenic mouse line that develops megabladder, obstructive uropathy, and renal dysfunction. J Am Soc Nephrol 18:461–471PubMedCrossRef
2.
go back to reference Singh S, Robinson M, Ismail I, Saha M, Auer H, Kornacker K, Robinson M, Bates C, McHugh KM (2008) Transcriptional profiling of the megabladder mouse—a unique model of bladder dysmorphogenesis. Dev Dyn 237:170–186PubMedCrossRef Singh S, Robinson M, Ismail I, Saha M, Auer H, Kornacker K, Robinson M, Bates C, McHugh KM (2008) Transcriptional profiling of the megabladder mouse—a unique model of bladder dysmorphogenesis. Dev Dyn 237:170–186PubMedCrossRef
3.
go back to reference Greenfield S, Hensle T, Berdon W, Wigger H (1983) Unilateral vesicoureteral reflux and unilateral nonfunctioning kidney associated with posterior urethral valves–a syndrome? J Urol 130:733–738PubMed Greenfield S, Hensle T, Berdon W, Wigger H (1983) Unilateral vesicoureteral reflux and unilateral nonfunctioning kidney associated with posterior urethral valves–a syndrome? J Urol 130:733–738PubMed
4.
go back to reference Kousidis G, Thomas D, Morgan H, Haider N, Subramaniam R, Feather S (2008) The long-term outcome of prenatally detected posterior urethral valves: a 10 to 23-year follow-up study. BJU Int 102:1020–1024PubMedCrossRef Kousidis G, Thomas D, Morgan H, Haider N, Subramaniam R, Feather S (2008) The long-term outcome of prenatally detected posterior urethral valves: a 10 to 23-year follow-up study. BJU Int 102:1020–1024PubMedCrossRef
5.
go back to reference Sanna-Cherchi S, Ravani P, Corbani V, Parodi S, Haupt R, Piaggio G, Innocenti M, Somenzi D, Trivelli A, Caridi G, Izzi C, Scolari F, Mattioli G, Allegri L, Ghiggeri G (2009) Renal outcome in patients with congenital anomalies of the kidney and urinary tract. Kidney Int 76:528–533PubMedCrossRef Sanna-Cherchi S, Ravani P, Corbani V, Parodi S, Haupt R, Piaggio G, Innocenti M, Somenzi D, Trivelli A, Caridi G, Izzi C, Scolari F, Mattioli G, Allegri L, Ghiggeri G (2009) Renal outcome in patients with congenital anomalies of the kidney and urinary tract. Kidney Int 76:528–533PubMedCrossRef
6.
go back to reference Ansari M, Gulia A, Srivastava A, Kapoor R (2010) Risk factors for progression to end-stage renal disease in children with posterior urethral valves. J Pediatr Urol 6:261–264PubMedCrossRef Ansari M, Gulia A, Srivastava A, Kapoor R (2010) Risk factors for progression to end-stage renal disease in children with posterior urethral valves. J Pediatr Urol 6:261–264PubMedCrossRef
7.
go back to reference Kleinjan D, Lettice L (2008) Long-range gene control and genetic disease. Advs Genet 61:340–388 Kleinjan D, Lettice L (2008) Long-range gene control and genetic disease. Advs Genet 61:340–388
8.
go back to reference Loots G, Kneissel M, Keller H, Baptist M, Chang J, Collette N, Ovcharenko D, Plajzer-Frick L, Rubin E (2005) Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchen disease. Gen Res 15:928–935CrossRef Loots G, Kneissel M, Keller H, Baptist M, Chang J, Collette N, Ovcharenko D, Plajzer-Frick L, Rubin E (2005) Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchen disease. Gen Res 15:928–935CrossRef
9.
go back to reference Fukami M, Okuyama T, Yamamori S, Nishimura G, Ogata T (2005) Microdeletion in the SHOX3’ region associated with skeletal phenotypes of Langer mesomelic dysplasia in a 45, X/46, X, r(X) infant and Leri-Weill dyschondrosteosis in her 46, XX mother: implications for the SHOX enhancer. Am J Med Genet 137:72–76PubMedCrossRef Fukami M, Okuyama T, Yamamori S, Nishimura G, Ogata T (2005) Microdeletion in the SHOX3’ region associated with skeletal phenotypes of Langer mesomelic dysplasia in a 45, X/46, X, r(X) infant and Leri-Weill dyschondrosteosis in her 46, XX mother: implications for the SHOX enhancer. Am J Med Genet 137:72–76PubMedCrossRef
10.
go back to reference Cai J, Goodman B, Patel A, Muliken J, Van Maldergem L, Hoganson G, Paznekas W, Ben Neriah Z, Sheiffer R, Cunningham M, Daentl D, Jabs E (2003) Increased risk for developmental delay in Saethre-Chotzen syndrome is associated with TWIST deletions: an improved strategy for TWIST mutation screening. Hum Genet 114:68–76PubMedCrossRef Cai J, Goodman B, Patel A, Muliken J, Van Maldergem L, Hoganson G, Paznekas W, Ben Neriah Z, Sheiffer R, Cunningham M, Daentl D, Jabs E (2003) Increased risk for developmental delay in Saethre-Chotzen syndrome is associated with TWIST deletions: an improved strategy for TWIST mutation screening. Hum Genet 114:68–76PubMedCrossRef
11.
go back to reference Bowl M, Nesbit M, Harding B, Levy E, Jefferson A, Volpi E, Rizzoti K, Lovell-Badge R, Schlessinger D, Whyte M, Thakker R (2005) An interstitial deletion-insertion involving chromosomes 2p25.3 and Xq27.1, near SOX3 causes X-linked recessive hypoparathyroidism. J Clin Invest 115:2822–2831PubMedCentralPubMedCrossRef Bowl M, Nesbit M, Harding B, Levy E, Jefferson A, Volpi E, Rizzoti K, Lovell-Badge R, Schlessinger D, Whyte M, Thakker R (2005) An interstitial deletion-insertion involving chromosomes 2p25.3 and Xq27.1, near SOX3 causes X-linked recessive hypoparathyroidism. J Clin Invest 115:2822–2831PubMedCentralPubMedCrossRef
12.
go back to reference Trembath GD, Semina EV, Jones DH, Patil SR, Qian Q, Amendt BA, Russo AF, Murray JC (2004) Analysis of two translocation breakpoints and identification of a negative regulatory element in patients with Rieger’s syndrome. Birth Defects Res Part A Clin Mol Teratol 70:82–91PubMedCrossRef Trembath GD, Semina EV, Jones DH, Patil SR, Qian Q, Amendt BA, Russo AF, Murray JC (2004) Analysis of two translocation breakpoints and identification of a negative regulatory element in patients with Rieger’s syndrome. Birth Defects Res Part A Clin Mol Teratol 70:82–91PubMedCrossRef
13.
go back to reference Wild A, Kaliff-Suske M, Vortkamp A, Bornholdt D, Konig R, Grzeschik K (1997) Point mutations in human GLI3 cause Greig syndrome. Hum Mol Genet 6:1979–1984PubMedCrossRef Wild A, Kaliff-Suske M, Vortkamp A, Bornholdt D, Konig R, Grzeschik K (1997) Point mutations in human GLI3 cause Greig syndrome. Hum Mol Genet 6:1979–1984PubMedCrossRef
14.
go back to reference De Kok Y, Vossenaar E, Cremers C, Dahl N, Laporte J, Hu L, Lacombe D, Fischel-Ghodsian N, Friedman R, Parnes L, Thorpe P, Bitner-Glindez M, Pander H, Heilbronner H, Graveline J, den Dunnen J, Brunner H, Ropers H, Cremers F (1996) Identification of a hot spot for microdeletions in patients with X-linked deafness type 3 (DFN3) 900 kb proximal to the DFN3 gene POU3F4. Hum Mol Genet 5:1229–1235PubMedCrossRef De Kok Y, Vossenaar E, Cremers C, Dahl N, Laporte J, Hu L, Lacombe D, Fischel-Ghodsian N, Friedman R, Parnes L, Thorpe P, Bitner-Glindez M, Pander H, Heilbronner H, Graveline J, den Dunnen J, Brunner H, Ropers H, Cremers F (1996) Identification of a hot spot for microdeletions in patients with X-linked deafness type 3 (DFN3) 900 kb proximal to the DFN3 gene POU3F4. Hum Mol Genet 5:1229–1235PubMedCrossRef
15.
go back to reference Becknell B, Carpenter A, Allen J, Wilhide M, Ingraham S, Hains D, McHugh KM (2013) Molecular basis of renal adaptation in a murine model of congenital obstructive nephropathy. PLoS One 8(9):e72762PubMedCentralPubMedCrossRef Becknell B, Carpenter A, Allen J, Wilhide M, Ingraham S, Hains D, McHugh KM (2013) Molecular basis of renal adaptation in a murine model of congenital obstructive nephropathy. PLoS One 8(9):e72762PubMedCentralPubMedCrossRef
16.
go back to reference Ingraham S, Saha M, Carpenter A, Robinson M, Ismail I, Singh S, Hains D, Robinson M, Hirselj D, Koff S, Bates C, McHugh KM (2010) Pathogenesis of renal injury in the megabladder mouse: a genetic model of congenital obstructive nephropathy. Pediatr Res 68:500–507PubMedCentralPubMedCrossRef Ingraham S, Saha M, Carpenter A, Robinson M, Ismail I, Singh S, Hains D, Robinson M, Hirselj D, Koff S, Bates C, McHugh KM (2010) Pathogenesis of renal injury in the megabladder mouse: a genetic model of congenital obstructive nephropathy. Pediatr Res 68:500–507PubMedCentralPubMedCrossRef
17.
go back to reference Inazaki K, Kanamaru Y, Kojima Y, Sueyoshi N, Okumura K, Kaneko K, Yamahiro Y, Igawa H, Nakao A (2004) Smad3 deficiency attenuates renal fibrosis, inflammation, and apoptosis after unilateral ureteral obstruction. Kidney Int 66:597–604PubMedCrossRef Inazaki K, Kanamaru Y, Kojima Y, Sueyoshi N, Okumura K, Kaneko K, Yamahiro Y, Igawa H, Nakao A (2004) Smad3 deficiency attenuates renal fibrosis, inflammation, and apoptosis after unilateral ureteral obstruction. Kidney Int 66:597–604PubMedCrossRef
18.
go back to reference Sato M, Muragaki Y, Saika S, Roberts A, Ooshima A (2003) Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. J Clin Invest 112:1486–1494PubMedCentralPubMedCrossRef Sato M, Muragaki Y, Saika S, Roberts A, Ooshima A (2003) Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. J Clin Invest 112:1486–1494PubMedCentralPubMedCrossRef
19.
go back to reference Furness P 3rd, Maizels M, Han S, Cohn R, Cheng E (1999) Elevated bladder urine concentration of transforming growth factor-beta1 correlates with upper urinary tract obstruction in children. J Urol 162:1033–1036PubMedCrossRef Furness P 3rd, Maizels M, Han S, Cohn R, Cheng E (1999) Elevated bladder urine concentration of transforming growth factor-beta1 correlates with upper urinary tract obstruction in children. J Urol 162:1033–1036PubMedCrossRef
20.
go back to reference Merlet-Benichou C, Vilar J, Lelievre-Pegorier M, Gilbert T (1999) Role of retinoids in renal development: pathophysiological implication. Curr Opin Nephr Hypertens 8:39–43CrossRef Merlet-Benichou C, Vilar J, Lelievre-Pegorier M, Gilbert T (1999) Role of retinoids in renal development: pathophysiological implication. Curr Opin Nephr Hypertens 8:39–43CrossRef
21.
go back to reference Batourina E, Choi C, Paragas N, Bello N, Hensle T, Costantini F, Schuchardt A, Bacallao R, Mendelsohn C (2002) Distal ureter morphogenesis depends on epithelial cell remodeling mediated by vitamin A and Ret. Nat Genet 32:109–115PubMedCrossRef Batourina E, Choi C, Paragas N, Bello N, Hensle T, Costantini F, Schuchardt A, Bacallao R, Mendelsohn C (2002) Distal ureter morphogenesis depends on epithelial cell remodeling mediated by vitamin A and Ret. Nat Genet 32:109–115PubMedCrossRef
22.
go back to reference Kishimoto K, Kinoshita K, Hino S, Yano T, Nagare Y, Shimazu H, Nozaki Y, Sugiyama M, Ikoma S, Funauchi M (2011) Therapeutic effect of retinoic acid on unilateral ureteral obstruction model. Nephron Exp Nephrol 118:e69–e78PubMedCrossRef Kishimoto K, Kinoshita K, Hino S, Yano T, Nagare Y, Shimazu H, Nozaki Y, Sugiyama M, Ikoma S, Funauchi M (2011) Therapeutic effect of retinoic acid on unilateral ureteral obstruction model. Nephron Exp Nephrol 118:e69–e78PubMedCrossRef
23.
go back to reference Schaier M, Jocks T, Grone H, Ritz E, Wagner J (2003) Retinoid agonist isotretinoin ameliorates obstructive renal injury. J Urol 170:1398–1402PubMedCrossRef Schaier M, Jocks T, Grone H, Ritz E, Wagner J (2003) Retinoid agonist isotretinoin ameliorates obstructive renal injury. J Urol 170:1398–1402PubMedCrossRef
24.
go back to reference Balasubramanian S, Jansen M, Valerius M, Humphreys B, Strom T (2012) Orphan nuclear receptor Nur77 promotes acute kidney injury and renal epithelial apoptosis. J Am Soc Nephrol 23:674–686PubMedCrossRef Balasubramanian S, Jansen M, Valerius M, Humphreys B, Strom T (2012) Orphan nuclear receptor Nur77 promotes acute kidney injury and renal epithelial apoptosis. J Am Soc Nephrol 23:674–686PubMedCrossRef
25.
go back to reference Scrocchi L, Hearn S, Han V, Hammond G (1993) Corticosteroid-binding globulin biosynthesis in the mouse liver and kidney during postnatal development. Endocrinology 132:910–916PubMed Scrocchi L, Hearn S, Han V, Hammond G (1993) Corticosteroid-binding globulin biosynthesis in the mouse liver and kidney during postnatal development. Endocrinology 132:910–916PubMed
26.
go back to reference Dokmanovic M, Clarke C, Marks PA (2007) Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res 5:981–989PubMedCrossRef Dokmanovic M, Clarke C, Marks PA (2007) Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res 5:981–989PubMedCrossRef
27.
go back to reference Ingelfinger J, Woods L (2002) Perinatal programming, renal development, and adult renal function. Am J Hypertens 15:46S–49SPubMedCrossRef Ingelfinger J, Woods L (2002) Perinatal programming, renal development, and adult renal function. Am J Hypertens 15:46S–49SPubMedCrossRef
28.
go back to reference Si H, Banga R, Kapitsinou P, Ramaiah M, Lawrence J, Kambhampati G, Gruenwald A, Bottinger E, Glicklich D, Tellis V, Greenstein S, Thomas D, Pullman J, Fazzari M, Susziak K (2009) Human and murine kidneys show gender- and species-specific gene expression differences in response to injury. PLoS One 4:e4802PubMedCentralPubMedCrossRef Si H, Banga R, Kapitsinou P, Ramaiah M, Lawrence J, Kambhampati G, Gruenwald A, Bottinger E, Glicklich D, Tellis V, Greenstein S, Thomas D, Pullman J, Fazzari M, Susziak K (2009) Human and murine kidneys show gender- and species-specific gene expression differences in response to injury. PLoS One 4:e4802PubMedCentralPubMedCrossRef
29.
go back to reference Metcalfe P, Meldrum K (2006) Sex differences and the role of sex steroids in renal injury. J Urol 176:15–21PubMedCrossRef Metcalfe P, Meldrum K (2006) Sex differences and the role of sex steroids in renal injury. J Urol 176:15–21PubMedCrossRef
30.
go back to reference Hutchens M, Dunlap J, Hurn P, Jarnberg P (2008) Renal ischemia: does sex matter? Anaesth Analg 107:239–429CrossRef Hutchens M, Dunlap J, Hurn P, Jarnberg P (2008) Renal ischemia: does sex matter? Anaesth Analg 107:239–429CrossRef
31.
go back to reference Seliger S, Davis C, Stehman-Breen C (2001) Gender and the progression of renal disease. Curr Opin Nephrol Hypertens 10:219–225PubMedCrossRef Seliger S, Davis C, Stehman-Breen C (2001) Gender and the progression of renal disease. Curr Opin Nephrol Hypertens 10:219–225PubMedCrossRef
32.
go back to reference Reyes D, Lew S, Kimmel P (2005) Gender differences in hypertension and kidney disease. Med Clin North Am 89:613–630PubMedCrossRef Reyes D, Lew S, Kimmel P (2005) Gender differences in hypertension and kidney disease. Med Clin North Am 89:613–630PubMedCrossRef
33.
go back to reference Delle H, Rocha J, Cavaglieri R, Vieira J Jr, Malheiros D, Noronha I (2012) Antifibrotic effect of tamoxifen in a model of progressive renal disease. J Am Soc Nephrol 23:37–48PubMedCrossRef Delle H, Rocha J, Cavaglieri R, Vieira J Jr, Malheiros D, Noronha I (2012) Antifibrotic effect of tamoxifen in a model of progressive renal disease. J Am Soc Nephrol 23:37–48PubMedCrossRef
34.
go back to reference Metcalfe P, Leslie J, Campbell M, Meldrum D, Hile K, Meldrum K (2008) Testosterone exacerbates obstructive renal injury by stimulating TNF-alpha production and increasing proapoptotic and profibrotic signaling. Am J Physiol Endocrin Metab 294: E435–E443CrossRef Metcalfe P, Leslie J, Campbell M, Meldrum D, Hile K, Meldrum K (2008) Testosterone exacerbates obstructive renal injury by stimulating TNF-alpha production and increasing proapoptotic and profibrotic signaling. Am J Physiol Endocrin Metab 294: E435–E443CrossRef
35.
go back to reference Becknell B, Carpenter A, Bolon B, Ingraham S, Hains D, Schwaderer A, McHugh KM (2013) Struvite urolithiasis and pyelonephritis associated with cutaneous vesicostomy in a murine model of functional lower urinary tract obstruction. Urology 81:943–948PubMedCentralPubMedCrossRef Becknell B, Carpenter A, Bolon B, Ingraham S, Hains D, Schwaderer A, McHugh KM (2013) Struvite urolithiasis and pyelonephritis associated with cutaneous vesicostomy in a murine model of functional lower urinary tract obstruction. Urology 81:943–948PubMedCentralPubMedCrossRef
Metadata
Title
Megabladder mouse model of congenital obstructive nephropathy: genetic etiology and renal adaptation
Author
Kirk M. McHugh
Publication date
01-04-2014
Publisher
Springer Berlin Heidelberg
Published in
Pediatric Nephrology / Issue 4/2014
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI
https://doi.org/10.1007/s00467-013-2658-6

Other articles of this Issue 4/2014

Pediatric Nephrology 4/2014 Go to the issue