title: A novel cell-permeable antioxidant peptide decreases renal tubular apoptosis and damage in unilateral ureteral obstruction.
abstract: Unilateral ureteral obstruction (UUO) is characterized by decreases in renal function, increased interstitial fibrosis, tubular apoptosis, and cellular infiltration. It has been suggested that inhibition of tubular apoptosis may protect against renal damage in obstruction. We have recently developed a series of peptides which are concentrated in the inner mitochondrial membrane and prevent cell death. These peptides are also active in vivo, in myocardial infraction, ischemic brain injury, and amyotrophic lateral sclerosis models. We therefore used SS-31, a prototype of these peptides, and assessed its effects on renal damage and oxidative stress in a 14-day obstruction model. SS-31 (1 or 3 mg/kg) or saline was given 1 day before and throughout the 14 days of obstruction. Kidneys were harvested and assessed for apoptosis (terminal transferase-dUTP-nick-end labeling, caspase 3 expression), fibrosis (trichrome staining), macrophage infiltration, fibroblast expression (immunoperoxidase), and oxidative damage (8-OH deoxyguanosine and heme oxygenase-1 expression), cytokines, and signaling pathways (transforming growth factor-beta, CCR-1, p38-MAPK, NF-kappaB). SS-31 significantly attenuated the effects of obstruction on all aspects of renal damage which were examined, with both the 1 and 3 mg/kg doses showing efficacy. We noted increased oxidative stress in obstruction, which was also attenuated by SS-31 treatment. Signaling via NF-kappaB and p38 MAPK pathways were both affected by SS-31 treatment. This study provides a proof of concept that peptides which protect mitochondria in vitro can provide protection from renal damage in a UUO model. The mechanism by which protection is afforded requires further studies both in vitro and in vivo.
authors.affiliation: Institute for Pediatric Urology, Department of Urology, Weill Medical College, 1300 York Ave., Box 94, New York, NY 10021, USA.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Mizuguchi
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Surya V
authors.initials: SV
authors.lastname: Seshan
authors.forename: Dix P
authors.initials: DP
authors.lastname: Poppas
authors.forename: Hazel H
authors.initials: HH
authors.lastname: Szeto
authors.forename: Diane
authors.initials: D
authors.lastname: Felsen
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D054389:Receptors, CCR1 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014517:Ureteral Obstruction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; C515302:Ccr1 protein, rat; D016207:Cytokines; D007381:Intermediate Filament Proteins; D009842:Oligopeptides; D054389:Receptors, CCR1; D051996:Transcription Factor RelA; D016212:Transforming Growth Factor beta; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide; D000080242:8-Hydroxy-2'-Deoxyguanosine; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases; D003849:Deoxyguanosine
references.citation: Am J Physiol Renal Physiol. 2006 Jan;290(1):F4-13
references.pmid: 16339963
references.citation: J Am Soc Nephrol. 2001 Feb;12(2):317-325
references.pmid: 11158221
references.citation: J Am Soc Nephrol. 2006 May;17(5):1373-81
references.pmid: 16597687
references.citation: Kidney Int. 2005 Mar;67(3):931-43
references.pmid: 15698432
references.citation: J Biol Chem. 2004 Aug 13;279(33):34682-90
references.pmid: 15178689
references.citation: J Am Soc Nephrol. 2005 Mar;16(3):667-75
references.pmid: 15677311
references.citation: Science. 2004 Jul 30;305(5684):626-9
references.pmid: 15286356
references.citation: J Am Soc Nephrol. 2007 Jan;18(1):213-22
references.pmid: 17151329
references.citation: J Am Soc Nephrol. 2004 Feb;15(2):337-47
references.pmid: 14747380
references.citation: Exp Neurol. 2006 Jun;199(2):513-9
references.pmid: 16480978
references.citation: J Urol. 2003 Apr;169(4):1559-63
references.pmid: 12629415
references.citation: Biochem Mol Med. 1997 Jun;61(1):82-6
references.pmid: 9232201
references.citation: Kidney Int. 2003 Jan;63(1):33-42
references.pmid: 12472766
references.citation: Kidney Int. 2001 Apr;59(4):1290-303
references.pmid: 11260390
references.citation: Kidney Int. 2005 Aug;68(2):515-28
references.pmid: 16014028
references.citation: J Pharmacol Exp Ther. 2003 Jan;304(1):425-32
references.pmid: 12490619
references.citation: Pediatr Nephrol. 2000 Aug;14(8-9):740-6
references.pmid: 10955918
references.citation: Biochim Biophys Acta. 1998 Dec 10;1448(2):190-9
references.pmid: 9920410
references.citation: Am J Physiol. 1997 Jun;272(6 Pt 2):F789-98
references.pmid: 9227641
references.citation: Nature. 2005 Jul 7;436(7047):123-7
references.pmid: 16001073
references.citation: J Urol. 2004 Jan;171(1):457-61
references.pmid: 14665955
references.citation: J Urol. 2000 Nov;164(5):1729-34
references.pmid: 11025760
references.citation: AAPS J. 2006 Apr 21;8(2):E277-83
references.pmid: 16796378
references.citation: Kidney Int. 2001 Jun;59(6):2095-103
references.pmid: 11380811
references.citation: Coron Artery Dis. 2007 May;18(3):215-20
references.pmid: 17429296
references.citation: Kidney Int. 2001 Sep;60(3):924-34
references.pmid: 11532087
references.citation: Kidney Int. 2000 Dec;58(6):2301-13
references.pmid: 11115064
references.citation: Kidney Int. 1999 Sep;56(3):1004-13
references.pmid: 10469368
references.citation: J Biol Chem. 2007 Feb 16;282(7):4634-4642
references.pmid: 17178711
references.citation: Urology. 2000 Aug 1;56(2):346-51
references.pmid: 10925121
references.citation: J Neurochem. 2006 Aug;98(4):1141-8
references.pmid: 16895581
references.citation: Am J Physiol Renal Physiol. 2002 Nov;283(5):F861-75
references.pmid: 12372761
references.citation: J Clin Invest. 2002 Aug;110(3):341-50
references.pmid: 12163453
references.citation: J Cell Biol. 1995 Jul;130(2):393-405
references.pmid: 7615639
references.citation: Exp Nephrol. 2001 Mar-Apr;9(2):71-80
references.pmid: 11150855
references.citation: Am J Physiol Renal Physiol. 2007 Apr;292(4):F1291-301
references.pmid: 17164399
references.citation: Am J Physiol Renal Physiol. 2004 Jun;286(6):F1030-8
references.pmid: 14722014
references.citation: Am J Physiol Heart Circ Physiol. 2002 Aug;283(2):H783-91
references.pmid: 12124228
references.citation: FASEB J. 2003 Oct;17(13):1972-4
references.pmid: 12923074
references.citation: Biochem Pharmacol. 2005 Dec 5;70(12):1796-806
references.pmid: 16216225
references.citation: Annu Rev Pharmacol Toxicol. 2007;47:629-56
references.pmid: 17014364