TY - JOUR
T1 - Proximal tubule epithelial cell specific ablation of the spermidine/spermine N1-acetyltransferase gene reduces the severity of renal ischemia/reperfusion injury
AU - Zahedi, Kamyar
AU - Barone, Sharon
AU - Wang, Yang
AU - Murray-Stewart, Tracy
AU - Roy-Chaudhury, Prabir
AU - Smith, Roger D.
AU - Casero, Robert A.
AU - Soleimani, Manoocher
N1 - Funding Information:
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.
Publisher Copyright:
©2014 zahedi et al.
PY - 2014/11/12
Y1 - 2014/11/12
N2 - Background: Expression and activity of spermidine/spermine N 1-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-α (TNF-α), 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.
AB - Background: Expression and activity of spermidine/spermine N 1-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-α (TNF-α), 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.
UR - http://www.scopus.com/inward/record.url?scp=84911871738&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84911871738&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0110161
DO - 10.1371/journal.pone.0110161
M3 - Article
C2 - 25390069
AN - SCOPUS:84911871738
SN - 1932-6203
VL - 9
JO - PloS one
JF - PloS one
IS - 11
M1 - e110161
ER -