Proximal tubule epithelial cell specific ablation of the spermidine/spermine N1-acetyltransferase gene reduces the severity of renal ischemia/reperfusion injury.

Abstract

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-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.

• Authors: Kamyar Zahedi, Sharon Barone, Yang Wang, Tracy Murray-Stewart, Prabir Roy-Chaudhury, Roger D Smith, Robert A Casero Jr, Manoocher Soleimani
• Journal: PloS one (PLoS One) Vol. 9 Issue 11 Pg. e110161 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25390069 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Cytokines
• Polyamines
• Oxidoreductases Acting on CH-NH Group Donors
• polyamine oxidase
• Acetyltransferases
• diamine N-acetyltransferase

Topics

• Acetyltransferases (genetics)
• Animals
• Cytokines (biosynthesis)
• Epithelial Cells (metabolism)
• Genotype
• HEK293 Cells
• Humans
• Immunity, Innate
• Inflammation
• Kidney (pathology)
• Kidney Tubules, Proximal (cytology)
• Male
• Mice
• Mice, Knockout
• Neutrophils (metabolism)
• Oxidoreductases Acting on CH-NH Group Donors (chemistry)
• Polyamines (chemistry)
• Reperfusion Injury (pathology)