title: Interstitial calcinosis in renal papillae of genetically engineered mouse models: relation to Randall's plaques.
abstract: Genetically engineered mouse models (GEMMs) have been highly instrumental in elucidating gene functions and molecular pathogenesis of human diseases, although their use in studying kidney stone formation or nephrolithiasis remains relatively limited. This review intends to provide an overview of several knockout mouse models that develop interstitial calcinosis in the renal papillae. Included herein are mice deficient for Tamm-Horsfall protein (THP; also named uromodulin), osteopontin (OPN), both THP and OPN, Na(+)-phosphate cotransporter Type II (Npt2a) and Na(+)/H(+) exchanger regulatory factor (NHERF-1). The baseline information of each protein is summarized, along with key morphological features of the interstitial calcium deposits in mice lacking these proteins. Attempts are made to correlate the papillary interstitial deposits found in GEMMs with Randall's plaques, the latter considered precursors of idiopathic calcium stones in patients. The pathophysiology that underlies the renal calcinosis in the knockout mice is also discussed wherever information is available. Not all the knockout models are allocated equal space because some are more extensively characterized than others. Despite the inroads already made, the exact physiological underpinning, origin, evolution and fate of the papillary interstitial calcinosis in the GEMMs remain incompletely defined. Greater investigative efforts are warranted to pin down the precise role of the papillary interstitial calcinosis in nephrolithiasis using the existing models. Additionally, more sophisticated, second-generation GEMMs that allow gene inactivation in a time-controlled manner and "compound mice" that bear several genetic alterations are urgently needed, in light of mounting evidence that nephrolithiasis is a multifactorial, multi-stage and polygenic disease.
authors.affiliation: Departments of Urology and Pathology, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA, xue-ru.wu@med.nyu.edu.
authors.forename: Xue-Ru
authors.initials: XR
authors.lastname: Wu
mesh_terms: D000818:Animals; D002114:Calcinosis / Q000235:genetics*; D004195:Disease Models, Animal; D007674:Kidney Diseases / Q000235:genetics*; D007679:Kidney Medulla; D051379:Mice / Q000235:genetics; D018345:Mice, Knockout; D053495:Osteopontin / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics; D050610:Sodium-Phosphate Cotransporter Proteins, Type II / Q000235:genetics; D058949:Uromodulin / Q000235:genetics
chemical_list: D010750:Phosphoproteins; D017923:Sodium-Hydrogen Exchangers; D050610:Sodium-Phosphate Cotransporter Proteins, Type II; C548613:Umod protein, mouse; D058949:Uromodulin; C093376:sodium-hydrogen exchanger regulatory factor; D053495:Osteopontin
references.citation: World J Urol. 1997;15(3):186-94
references.pmid: 9228726
references.citation: J Clin Invest. 2003 Mar;111(5):607-16
references.pmid: 12618515
references.citation: Urol Clin North Am. 2013 Feb;40(1):1-12
references.pmid: 23177630
references.citation: Exp Oncol. 2004 Sep;26(3):179-84
references.pmid: 15494684
references.citation: Science. 1985 Aug 2;229(4712):479-81
references.pmid: 2409603
references.citation: Annu Rev Nutr. 2005;25:197-214
references.pmid: 16011465
references.citation: Am J Kidney Dis. 2003 Oct;42(4):658-76
references.pmid: 14520616
references.citation: Curr Opin Nephrol Hypertens. 2006 Jul;15(4):374-80
references.pmid: 16775451
references.citation: Kidney Int. 2008 Apr;73(8):971-6
references.pmid: 18004297
references.citation: J Clin Invest. 2005 Oct;115(10):2598-608
references.pmid: 16200192
references.citation: N Engl J Med. 2002 Sep 26;347(13):983-91
references.pmid: 12324554
references.citation: Cancer Res. 2012 Jun 1;72(11):2695-700
references.pmid: 22593194
references.citation: Biosci Rep. 1984 Mar;4(3):269-74
references.pmid: 6722291
references.citation: Urol J. 2005 Spring;2(2):79-85
references.pmid: 17629875
references.citation: J Urol. 2007 Jan;177(1):31-8
references.pmid: 17161996
references.citation: J Urol. 2005 Sep;174(3):943-7; discussion 947
references.pmid: 16094002
references.citation: J Am Soc Nephrol. 1994 Nov;5(5 Suppl 1):S37-45
references.pmid: 7873743
references.citation: Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9630-5
references.pmid: 8790381
references.citation: Eur J Clin Invest. 2008 Oct;38 Suppl 2:29-38
references.pmid: 18826479
references.citation: J Clin Invest. 2005 Dec;115(12):3613-22
references.pmid: 16308573
references.citation: Kidney Int. 2005 Feb;67(2):576-91
references.pmid: 15673305
references.citation: J Am Soc Nephrol. 2003 Jan;14(1):139-47
references.pmid: 12506146
references.citation: Am J Physiol Endocrinol Metab. 2004 May;286(5):E686-96
references.pmid: 15102615
references.citation: Am J Kidney Dis. 2012 Mar;59(3):452-61
references.pmid: 22277744
references.citation: Clin Immunol. 2009 Apr;131(1):84-91
references.pmid: 19138884
references.citation: Urol Clin North Am. 2007 Aug;34(3):323-34
references.pmid: 17678983
references.citation: Int J Immunopathol Pharmacol. 2010 Jan-Mar;23(1):263-9
references.pmid: 20378012
references.citation: Urol Res. 2012 Dec;40(6):623-37
references.pmid: 23124115
references.citation: Am J Physiol Renal Physiol. 2010 Aug;299(2):F387-95
references.pmid: 20427471
references.citation: Scand J Urol Nephrol. 2008;42(2):168-74
references.pmid: 17907053
references.citation: Urol Int. 1986;41(5):329-33
references.pmid: 3544437
references.citation: Am J Physiol Renal Physiol. 2007 Dec;293(6):F1935-43
references.pmid: 17898038
references.citation: Kidney Int. 2001 Nov;60(5):1645-57
references.pmid: 11703581
references.citation: J Biol Chem. 2012 Jan 6;287(2):1290-305
references.pmid: 22117067
references.citation: Nephron Physiol. 2004;98(2):p43-7
references.pmid: 15499214
references.citation: QJM. 2005 Apr;98(4):241-6
references.pmid: 15781479
references.citation: J Cell Sci. 2001 Nov;114(Pt 22):4095-103
references.pmid: 11739641
references.citation: Am J Physiol Renal Physiol. 2008 May;294(5):F1109-15
references.pmid: 18337544
references.citation: Urol Res. 2011 Aug;39(4):269-82
references.pmid: 21229239
references.citation: Kidney Int. 2008 Aug;74(4):427-37
references.pmid: 18418351
references.citation: J Biol Chem. 2012 May 11;287(20):16365-78
references.pmid: 22451664
references.citation: Urol Int. 2002;68(1):54-9
references.pmid: 11803269
references.citation: FEBS Lett. 2004 Dec 17;578(3):236-8
references.pmid: 15589826
references.citation: Science. 1987 Sep 18;237(4821):1479-84
references.pmid: 3498215
references.citation: Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11470-5
references.pmid: 12169661
references.citation: J Am Soc Nephrol. 1999 Nov;10 Suppl 14:S417-21
references.pmid: 10541276
references.citation: Kidney Int. 2004 Sep;66(3):1159-66
references.pmid: 15327412
references.citation: Urol Res. 2007 Apr;35(2):55-62
references.pmid: 17345077
references.citation: Am J Physiol. 1989 Jul;257(1 Pt 2):F99-106
references.pmid: 2750929
references.citation: Nephrol Dial Transplant. 2014 Jan;29(1):136-45
references.pmid: 24097801
references.citation: Am J Physiol Renal Physiol. 2008 Apr;294(4):F840-9
references.pmid: 18216150
references.citation: Am J Physiol Renal Physiol. 2013 Apr 15;304(8):F1066-75
references.pmid: 23389456
references.citation: Nat Rev Cancer. 2005 Sep;5(9):713-25
references.pmid: 16110317
references.citation: Kidney Int. 2004 Mar;65(3):791-7
references.pmid: 14871399
references.citation: Nat Cell Biol. 2002 Jun;4(6):457-61
references.pmid: 12021773
references.citation: Ann Surg. 1937 Jun;105(6):1009-27
references.pmid: 17856988
references.citation: Endocrinol Metab Clin North Am. 2002 Dec;31(4):869-84
references.pmid: 12474635
references.citation: J Am Soc Nephrol. 2008 Sep;19(9):1753-62
references.pmid: 18550648
references.citation: Front Biosci. 2004 May 01;9:1450-82
references.pmid: 14977559
references.citation: QJM. 2002 Jan;95(1):3-13
references.pmid: 11834767
references.citation: Urol Res. 2010 Dec;38(6):439-52
references.pmid: 21063698
references.citation: Lancet. 2006 Jan 28;367(9507):333-44
references.pmid: 16443041
references.citation: Cancer Metastasis Rev. 2009 Dec;28(3-4):281-90
references.pmid: 20012171
references.citation: Mol Urol. 2001 Spring;5(1):1-5
references.pmid: 11689144
references.citation: Kidney Int. 2005 Oct;68(4):1784-92
references.pmid: 16164655
references.citation: Semin Nephrol. 2010 Jul;30(4):366-73
references.pmid: 20807609
references.citation: J Bone Miner Res. 1995 Dec;10(12):1913-29
references.pmid: 8619372
references.citation: Am J Kidney Dis. 1994 Dec;24(6):893-900
references.pmid: 7985666
references.citation: Eur J Biochem. 1998 May 1;253(3):637-44
references.pmid: 9654060
references.citation: Exp Nephrol. 1999 Mar-Apr;7(2):103-13
references.pmid: 10213864
references.citation: Am J Physiol Renal Physiol. 2006 Apr;290(4):F838-43
references.pmid: 16249272
references.citation: Curr Opin Nephrol Hypertens. 1996 Jul;5(4):342-6
references.pmid: 8823532
references.citation: Clin Biochem. 1997 Feb;30(1):63-7
references.pmid: 9056112
references.citation: Curr Opin Nephrol Hypertens. 2006 Jul;15(4):403-18
references.pmid: 16775455
references.citation: Scand J Urol Nephrol. 2010 Dec;44(6):438-44
references.pmid: 20624112
references.citation: Science. 1987 Apr 3;236(4797):83-8
references.pmid: 3453112
references.citation: Am J Physiol Renal Physiol. 2006 Dec;291(6):F1123-31
references.pmid: 17082348
references.citation: Glycobiology. 1999 Jan;9(1):21-30
references.pmid: 9884403
references.citation: Glycoconj J. 2005 Nov;22(7-9):383-94
references.pmid: 16622944
references.citation: Am J Physiol Renal Physiol. 2008 Aug;295(2):F534-44
references.pmid: 18495803
references.citation: J Biol Chem. 2004 Jan 2;279(1):216-22
references.pmid: 14570881
references.citation: Miner Electrolyte Metab. 1994;20(6):393-8
references.pmid: 7783702
references.citation: J Gastroenterol. 2005 Apr;40(4):381-8
references.pmid: 15868370
references.citation: Curr Opin Urol. 1998 Jul;8(4):315-9
references.pmid: 17038975
references.citation: PLoS One. 2012;7(4):e34764
references.pmid: 22506049
references.citation: Matrix Biol. 2000 Dec;19(7):615-22
references.pmid: 11102750
references.citation: BMC Cancer. 2012 Oct 16;12:477
references.pmid: 23072570
references.citation: Kidney Int. 2011 Aug;80(4):338-47
references.pmid: 21654721
references.citation: Am J Physiol Renal Physiol. 2011 Apr;300(4):F999-1007
references.pmid: 21228114
references.citation: Am J Physiol Renal Physiol. 2010 Sep;299(3):F469-78
references.pmid: 20591941
references.citation: Am J Kidney Dis. 2004 Dec;44(6):987-99
references.pmid: 15558519
references.citation: PLoS Genet. 2010 Jul 29;6(7):e1001039
references.pmid: 20686651
references.citation: Kidney Int. 1990 Jun;37(6):1395-401
references.pmid: 2194064
references.citation: Nephrol Dial Transplant. 2000 Oct;15(10):1580-7
references.pmid: 11007825
references.citation: Cancer Res. 2009 Dec 15;69(24):9413-21
references.pmid: 19951992
references.citation: J Urol. 2011 Sep;186(3):1107-13
references.pmid: 21784483
references.citation: J Clin Endocrinol Metab. 2012 Jun;97(6):1847-60
references.pmid: 22466339
references.citation: J Biol Chem. 2001 Mar 30;276(13):9924-30
references.pmid: 11134021
references.citation: Clin Chim Acta. 1986 Aug 15;158(3):229-35
references.pmid: 2429785
references.citation: Kidney Int. 2013 Jul;84(1):130-7
references.pmid: 23466996
references.citation: Urol Res. 1998;26(3):201-7
references.pmid: 9694603
references.citation: Urol Res. 1992;20(1):83-6
references.pmid: 1736492
references.citation: Am J Physiol Renal Physiol. 2004 Apr;286(4):F795-802
references.pmid: 14665435
references.citation: J Am Soc Nephrol. 2003 Jul;14(7):1711-9
references.pmid: 12819230
references.citation: Semin Nephrol. 1996 Sep;16(5):474-86
references.pmid: 8890402
references.citation: Am J Physiol Renal Physiol. 2005 Jul;289(1):F49-60
references.pmid: 15741608
references.citation: Urol Res. 2004 May;32(2):79-83
references.pmid: 15250099
references.citation: Kidney Int. 2003 Nov;64(5):1733-45
references.pmid: 14531806
references.citation: Kidney Int. 2009 Jun;75(11):1153-1165
references.pmid: 19340092
references.citation: Urolithiasis. 2013 Aug;41(4):303-13
references.pmid: 23784265
references.citation: J Clin Invest. 1998 Apr 1;101(7):1468-78
references.pmid: 9525990
references.citation: Curr Opin Nephrol Hypertens. 2000 Jul;9(4):349-55
references.pmid: 10926170
references.citation: Transgenic Res. 2012 Apr;21(2):327-49
references.pmid: 21800101
references.citation: Urol Res. 2012 Apr;40(2):95-112
references.pmid: 22213019
references.citation: Physiol Genomics. 2002 Dec 3;11(3):115-32
references.pmid: 12464688
references.citation: Clin Chem. 1994 Sep;40(9):1739-43
references.pmid: 8070085
references.citation: Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5372-7
references.pmid: 9560283