The complex structural and functional organization of the kidneys as well as the heterogeneity of underlying etiologies of kidney disease complicate therapy. Treatment might benefit from the identification of common disease mechanisms that are shared by various kidney pathologies. The polyamine system is a highly conserved network consisting of the biogenic polyamines putrescine, spermidine, and spermine. Polyamines are organic polycationic molecules with several amino groups. Because of their positive charge, polyamines can bind to proteins and nucleic acids, thereby influencing a plethora of cellular processes. The polyamine homeostasis is frequently dysregulated in acute and chronic renal pathologies. As polyamines are involved in injury and repair in different organs, the hypothesis is tested that different forms of renal injury lead to a similar dysregulation of the polyamine system and that changing polyamine levels have an influence on the severity of renal injury. Eleven different animal models of acute and chronic kidney injury with various etiologies were used. Among these models, a similar pattern of polyamine dysregulation was observed. While the polyamine synthesizing genes Odc1, Srm and Sms are downregulated, polyamine catabolism by Aoc1, Smox or Sat1 is upregulated after injury. Here, ODC1 and AOC1, which can synthesize and degrade putrescine respectively show the most prominent changes. While Odc1 is strongly expressed in healthy kidneys, Aoc1 shows little expression. After injury however the expression shifts with Aoc1 strongly increasing and Odc1 being reduced. Within the injured kidney, AOC1 is necessary for degradation of putrescine and ablation of Aoc1 increases renal putrescine levels after injury. Different stimuli, leading to increased Aoc1 expression were assessed and hyperosmolarity was found as a strong stimulus. Hyperosmolarity stimulates transcription of Aoc1 involving NFAT5 and also stabilizes Aoc1 mRNA.The transcriptional activation is initiated at a promoter element of a certain isoform, containing additional N-terminal amino acids, leading to increased secretion. Using a germline deletion of Aoc1 in mice, it was tested whether ablation of Aoc1 changes the outcome of kidney injury. Here, only mild improvements were detected, including the reduction of intratubular casts after ischemia-reperfusion injury. These data show that various types of acute and chronic kidney injury result in a similar dysregulation of the polyamine system with inhibition of polyamine synthesis and activation of polyamine breakdown. Furthermore, it is shown that polyamine homeostasis influences regeneration after renal injury.
