title: Proteinuria and hyperglycemia induce endoplasmic reticulum stress.
abstract: The endoplasmic reticulum (ER) is an important site for protein folding and becomes "stressed" when its capacity to fold proteins is overwhelmed. In response, "unfolded protein response" (UPR) genes are induced, increasing the capacity to fold proteins; if the response is insufficient, then apoptosis ensues. For investigation of whether proteinuria and hyperglycemia induce ER stress in renal epithelial cells, microarray data from biopsies of established diabetic nephropathy (DN) were analyzed. Expression of UPR genes was significantly different in these biopsies than in control kidneys or biopsies of patients with mild DN, suggesting an association between the degree of DN and UPR gene expression. Expression of the transcription factor XBP1 and the ER chaperones HSPA5 and HYOU1 were increased, but the proapoptotic gene DDIT3 was unchanged. These findings were replicated in an independent cohort of patients with established DN by real-time reverse transcriptase-PCR. Immunofluorescence of renal biopsies from patients with DN confirmed the upregulation for HSPA5 and HYOU1 proteins in tubular epithelia. In biopsies of minimal-change disease, the mRNA levels of some ER stress molecules were also induced, but protein expression of HSPA5 and HYOU1 remained significantly lower than that observed in DN. Exposure of renal tubular epithelial cells to albumin and high glucose in vitro enhanced expression of genes involved in ER stress. These observations suggest that in proteinuric diseases, tubular epithelial cells undergo ER stress, which induces an adaptive, protective UPR. Although this may protect the cells from ER stress, persistence of hyperglycemia and proteinuria may eventually lead to apoptosis.
authors.affiliation: Nephrology Center, Medizinische Poliklinik, University of Munich, Munich, Germany.
authors.forename: Maja T
authors.initials: MT
authors.lastname: Lindenmeyer
authors.forename: Maria P
authors.initials: MP
authors.lastname: Rastaldi
authors.forename: Masami
authors.initials: M
authors.lastname: Ikehata
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Neusser
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.forename: Clemens D
authors.initials: CD
authors.lastname: Cohen
authors.forename: Detlef
authors.initials: D
authors.lastname: Schlöndorff
mesh_terms: D000418:Albumins / Q000494:pharmacology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism*; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D017510:Protein Folding; D011506:Proteins / Q000235:genetics; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D019284:Thapsigargin / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics; D014415:Tunicamycin / Q000494:pharmacology; D000071717:X-Box Binding Protein 1
chemical_list: D000418:Albumins; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D018840:HSP70 Heat-Shock Proteins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011506:Proteins; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C050087:oxygen-regulated proteins; D014415:Tunicamycin; D019284:Thapsigargin; D005947:Glucose
references.citation: Nephron. 1999;83(4):289-95
references.pmid: 10575289
references.citation: Kidney Int. 2006 Feb;69(3):440-9
references.pmid: 16514429
references.citation: J Clin Invest. 2002 Feb;109(4):525-32
references.pmid: 11854325
references.citation: J Biol Chem. 2002 Nov 1;277(44):41342-51
references.pmid: 12191998
references.citation: J Biol Chem. 2005 Jan 7;280(1):847-51
references.pmid: 15509553
references.citation: J Endocrinol. 2007 Apr;193(1):65-74
references.pmid: 17400804
references.citation: Kidney Int Suppl. 2002 Dec;(82):S42-6
references.pmid: 12410854
references.citation: Kidney Int. 2005 Dec;68(6):2639-50
references.pmid: 16316340
references.citation: Biol Pharm Bull. 2003 Jul;26(7):931-5
references.pmid: 12843613
references.citation: Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29
references.pmid: 17565364
references.citation: Intern Med. 2004 Jan;43(1):9-17
references.pmid: 14964574
references.citation: Am J Nephrol. 2005 Mar-Apr;25(2):77-94
references.pmid: 15746541
references.citation: Diabetes. 2006 Nov;55(11):2993-3003
references.pmid: 17065335
references.citation: Annu Rev Biochem. 2005;74:739-89
references.pmid: 15952902
references.citation: Mol Cell Biol. 2006 Apr;26(8):3071-84
references.pmid: 16581782
references.citation: Diabetes. 2002 Dec;51 Suppl 3:S455-61
references.pmid: 12475790
references.citation: Antioxid Redox Signal. 2007 Dec;9(12):2277-93
references.pmid: 17979528
references.citation: Med Res Rev. 2005 Nov;25(6):587-609
references.pmid: 16075407
references.citation: J Clin Invest. 2005 Oct;115(10):2656-64
references.pmid: 16200199
references.citation: Kidney Int. 2002 Jan;61(1):133-40
references.pmid: 11786093
references.citation: Exp Biol Med (Maywood). 2003 Nov;228(10):1213-7
references.pmid: 14610263
references.citation: J Am Soc Nephrol. 2004 Feb;15(2):380-9
references.pmid: 14747384
references.citation: FASEB J. 2004 Sep;18(12):1401-3
references.pmid: 15240565
references.citation: Genes Dev. 2004 Dec 15;18(24):3066-77
references.pmid: 15601821
references.citation: J Biol Chem. 2001 Mar 23;276(12):8623-6
references.pmid: 11254652
references.citation: Genes Cells. 2004 Mar;9(3):261-70
references.pmid: 15005713
references.citation: J Am Soc Nephrol. 2006 Nov;17(11):2974-84
references.pmid: 17035611
references.citation: PLoS Biol. 2006 Nov;4(11):e374
references.pmid: 17090218
references.citation: Kidney Int. 2006 Oct;70(8):1447-55
references.pmid: 16955111
references.citation: J Biol Chem. 2005 Jul 1;280(26):24396-403
references.pmid: 15863508
references.citation: Contrib Nephrol. 2005;148:8-20
references.pmid: 15912024
references.citation: Am J Kidney Dis. 2005 Oct;46(4):766-73
references.pmid: 16183435
references.citation: Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21
references.pmid: 11309499
references.citation: Kidney Int. 1999 Nov;56(5):1627-37
references.pmid: 10571771
references.citation: Trends Pharmacol Sci. 1998 Apr;19(4):131-5
references.pmid: 9612087
references.citation: Neurology. 2006 Jan 24;66(2 Suppl 1):S102-9
references.pmid: 16432136
references.citation: EMBO Rep. 2006 Sep;7(9):880-5
references.pmid: 16953201