Strikingly conserved gene expression changes of polyamine regulating enzymes among various forms of acute and chronic kidney injury

Tobias Sieckmann; Gunnar Schley; Neslihan Ögel; Simon Kelterborn; Felix J Boivin; Michael Fähling; Muhammad I Ashraf; Martin Reichel; Emilia Vigolo; Andrea Hartner; Falk-Bach Lichtenberger; Tilman Breiderhoff; Felix Knauf; Christian Rosenberger; Felix Aigner; Kai Schmidt-Ott; Holger Scholz; Karin M Kirschner

doi:10.1016/j.kint.2023.04.005

Strikingly conserved gene expression changes of polyamine regulating enzymes among various forms of acute and chronic kidney injury

Kidney Int. 2023 Jul;104(1):90-107. doi: 10.1016/j.kint.2023.04.005. Epub 2023 Apr 28.

Authors

Tobias Sieckmann¹, Gunnar Schley², Neslihan Ögel¹, Simon Kelterborn¹, Felix J Boivin³, Michael Fähling¹, Muhammad I Ashraf⁴, Martin Reichel⁵, Emilia Vigolo⁶, Andrea Hartner⁷, Falk-Bach Lichtenberger¹, Tilman Breiderhoff⁸, Felix Knauf⁵, Christian Rosenberger⁵, Felix Aigner⁹, Kai Schmidt-Ott¹⁰, Holger Scholz¹, Karin M Kirschner¹¹

Affiliations

¹ Institute of Translational Physiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
² Department of Nephrology and Hypertension, Friedrich-Alexander University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Erlangen, Germany.
³ Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; Molecular and Translational Kidney Research, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
⁴ Department of Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
⁵ Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
⁶ Molecular and Translational Kidney Research, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
⁷ Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander University Erlangen-Nürnberg (FAU), University Hospital Erlangen, Erlangen, Germany.
⁸ Department of Pediatrics, Division of Gastroenterology, Nephrology and Metabolic Diseases, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
⁹ Department of Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; Department of Surgery, St. John of God Hospital Graz, Graz, Austria.
¹⁰ Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany; Molecular and Translational Kidney Research, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.
¹¹ Institute of Translational Physiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. Electronic address: [email protected].

PMID: 37121432
DOI: 10.1016/j.kint.2023.04.005

Abstract

The polyamines spermidine and spermine and their common precursor molecule putrescine are involved in tissue injury and repair. Here, we test the hypothesis that impaired polyamine homeostasis contributes to various kidney pathologies in mice during experimental models of ischemia-reperfusion, transplantation, rhabdomyolysis, cyclosporine treatment, arterial hypertension, diabetes, unilateral ureteral obstruction, high oxalate feeding, and adenine-induced injuries. We found a remarkably similar pattern in most kidney pathologies with reduced expression of enzymes involved in polyamine synthesis together with increased expression of polyamine degrading enzymes. Transcript levels of amine oxidase copper-containing 1 (Aoc1), an enzyme which catalyzes the breakdown of putrescine, were barely detectable by in situ mRNA hybridization in healthy kidneys. Aoc1 was highly expressed upon various experimental kidney injuries resulting in a significant reduction of kidney putrescine content. Kidney levels of spermine were also significantly reduced, whereas spermidine was increased in response to ischemia-reperfusion injury. Increased Aoc1 expression in injured kidneys was mainly accounted for by an Aoc1 isoform that harbors 22 additional amino acids at its N-terminus and shows increased secretion. Mice with germline deletion of Aoc1 and injured kidneys showed no decrease of kidney putrescine content; although they displayed no overt phenotype, they had fewer tubular casts upon ischemia-reperfusion injury. Hyperosmotic stress stimulated AOC1 expression at the transcriptional and post-transcription levels in metanephric explants and kidney cell lines. AOC1 expression was also significantly enhanced after kidney transplantation in humans. These data demonstrate that the kidneys respond to various forms of injury with down-regulation of polyamine synthesis and activation of the polyamine breakdown pathway. Thus, an imbalance in kidney polyamines may contribute to various etiologies of kidney injury.

Keywords: Aoc1; kidney injury; mRNA in situ hybridization; osmotic stress; polyamines; putrescine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetyltransferases / genetics
Acetyltransferases / metabolism
Amine Oxidase (Copper-Containing)* / metabolism
Animals
Gene Expression
Humans
Kidney / pathology
Mice
Polyamines / metabolism
Putrescine / metabolism
Reperfusion Injury* / pathology
Spermidine / metabolism
Spermine / metabolism
Spermine / pharmacology

Substances

Polyamines
Spermidine
Putrescine
Spermine
Acetyltransferases
Amine Oxidase (Copper-Containing)