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

PLoS One. 2014 Nov 12;9(11):e110161. doi: 10.1371/journal.pone.0110161. eCollection 2014.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 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
  • Polyamine Oxidase
  • Polyamines / chemistry
  • Reperfusion Injury / pathology*

Substances

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