PMID- 25390069 OWN - NLM STAT- MEDLINE DCOM- 20150713 LR - 20231213 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 9 IP - 11 DP - 2014 TI - Proximal tubule epithelial cell specific ablation of the spermidine/spermine N1-acetyltransferase gene reduces the severity of renal ischemia/reperfusion injury. PG - e110161 LID - 10.1371/journal.pone.0110161 [doi] LID - e110161 AB - BACKGROUND: Expression and activity of spermidine/spermine N1-acetyltransferase (SSAT) increases in kidneys subjected to ischemia/reperfusion (I/R) injury, while its ablation reduces the severity of such injuries. These results suggest that increased SSAT levels contribute to organ injury; however, the role of SSAT specifically expressed in proximal tubule epithelial cells, which are the primary targets of I/R injury, in the mediation of renal damage remains unresolved. METHODS: Severity of I/R injury in wt and renal proximal tubule specific SSAT-ko mice (PT-SSAT-Cko) subjected to bilateral renal I/R injury was assessed using cellular and molecular biological approaches. RESULTS: Severity of the loss of kidney function and tubular damage are reduced in PT-SSAT-Cko- compared to wt-mice after I/R injury. In addition, animals treated with MDL72527, an inhibitor of polyamine oxidases, had less severe renal damage than their vehicle treated counter-parts. The renal expression of HMGB 1 and Toll like receptors (TLR) 2 and 4 were also reduced in PT-SSAT-Cko- compared to wt mice after I/R injury. Furthermore, infiltration of neutrophils, as well as expression of tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6) transcripts were lower in the kidneys of PT-SSAT-Cko compared to wt mice after I/R injury. Finally, the activation of caspase3 was more pronounced in the wt compared to PT-SSAT-Cko animals. CONCLUSIONS: Enhanced SSAT expression by proximal tubule epithelial cells leads to tubular damage, and its deficiency reduces the severity of renal I/R injury through reduction of cellular damage and modulation of the innate immune response. FAU - Zahedi, Kamyar AU - Zahedi K AD - Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America; Veterans Affair Medical Center, Cincinnati, Ohio, United States of America. FAU - Barone, Sharon AU - Barone S AD - Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America; Veterans Affair Medical Center, Cincinnati, Ohio, United States of America. FAU - Wang, Yang AU - Wang Y AD - Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America. FAU - Murray-Stewart, Tracy AU - Murray-Stewart T AD - The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. FAU - Roy-Chaudhury, Prabir AU - Roy-Chaudhury P AD - Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America. FAU - Smith, Roger D AU - Smith RD AD - Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America. FAU - Casero, Robert A Jr AU - Casero RA Jr AD - The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. FAU - Soleimani, Manoocher AU - Soleimani M AD - Division of Nephrology and Hypertension, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America; Veterans Affair Medical Center, Cincinnati, Ohio, United States of America. LA - eng GR - R01 CA051085/CA/NCI NIH HHS/United States GR - R01 CA098454/CA/NCI NIH HHS/United States GR - CA098454/CA/NCI NIH HHS/United States GR - CA051085/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20141112 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Cytokines) RN - 0 (Polyamines) RN - EC 1.5.- (Oxidoreductases Acting on CH-NH Group Donors) RN - EC 2.3.1.- (Acetyltransferases) RN - EC 2.3.1.57 (diamine N-acetyltransferase) SB - IM MH - Acetyltransferases/*genetics MH - Animals MH - Cytokines/biosynthesis MH - Epithelial Cells/*metabolism MH - Genotype MH - HEK293 Cells MH - Humans MH - Immunity, Innate MH - Inflammation MH - Kidney/*pathology MH - Kidney Tubules, Proximal/*cytology MH - Male MH - Mice MH - Mice, Knockout MH - Neutrophils/metabolism MH - Oxidoreductases Acting on CH-NH Group Donors/chemistry MH - Polyamines/chemistry MH - Reperfusion Injury/*pathology MH - Polyamine Oxidase PMC - PMC4229091 COIS- Competing Interests: This study was supported by funds from Dialysis Clinic Inc. and US Renal Care Inc. There are no patents, products in development or marketed products to declare. Provision of funds by Dialysis Clinic Inc. and US Renal Care Inc. does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. EDAT- 2014/11/13 06:00 MHDA- 2015/07/15 06:00 PMCR- 2014/11/12 CRDT- 2014/11/13 06:00 PHST- 2014/06/11 00:00 [received] PHST- 2014/09/09 00:00 [accepted] PHST- 2014/11/13 06:00 [entrez] PHST- 2014/11/13 06:00 [pubmed] PHST- 2015/07/15 06:00 [medline] PHST- 2014/11/12 00:00 [pmc-release] AID - PONE-D-14-26151 [pii] AID - 10.1371/journal.pone.0110161 [doi] PST - epublish SO - PLoS One. 2014 Nov 12;9(11):e110161. doi: 10.1371/journal.pone.0110161. eCollection 2014.