Kidney Week

Abstract: TH-PO951

Genetic Ablation of Spermidine Oxidase Leads to Blunted Production of the Uremic Toxin Acrolein but Does Not Prevent CKD

Session Information

• Molecular Mechanisms of CKD - I
  October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 1903 CKD (Non-Dialysis): Mechanisms

Authors

• Bamberg, Krister, AstraZeneca, Gothenburg, Sweden

Krister Bamberg,

• Ericson, Charlotte, AstraZeneca, Gothenburg, Sweden

Charlotte Ericson,

• Löfgren, Lars, AstraZeneca, Gothenburg, Sweden

Lars Löfgren,

• Basta, Barbro, AstraZeneca, Gothenburg, Sweden

Barbro Basta,

• Madeyski-Bengtson, Katja, AstraZeneca, Gothenburg, Sweden

Katja Madeyski-Bengtson,

• Maresca, Marcello, AstraZeneca, Gothenburg, Sweden

Marcello Maresca,

• Inui, Yosuke, Mitsubishi Tanabe Pharma Corporation, Toda, Saitama, Japan

Yosuke Inui,

• Mochida, Hideki, Mitsubishi Tanabe Pharma Corporation, Toda, Saitama, Japan

Hideki Mochida,

• Fjellström, Ola, AstraZeneca, Gothenburg, Sweden

Ola Fjellström,

Background

The uremic toxin acrolein, a highly reactive aldehyde, is associated with cardiovascular disease and has been linked to chronic kidney disease (CKD). Sources of acrolein include e.g. smoking, lipid peroxidation and spermine metabolism. Spermine oxidase (SMOX) converts spermine to spermidine and generates acrolein.

Methods

Spermine oxidase germline deficient mice (SMOX-/-) were generated by CRISPR mediated gene deletion. Mice were subjected to an LPS challenge to study acute effects on polyamine and acrolein production. To study more chronic effects, renal ischemia reperfusion injury (IRI) or adenine diet induced kidney injury were elicited. 3HPMA, a stable metabolite of glutathione adducted acrolein, was measured in plasma and organs to assess acrolein production.

Results

SMOX deletion resulted in reduced circulating spermidine and acrolein levels. Following an LPS challenge, the acutely elevated acrolein levels, but also plasma creatinine levels particularly in males, were blunted in SMOX-/- animals. Both renal IRI and adenine diet induced chronic kidney injury led to increased circulating levels of acrolein in wild type but not in SMOX-/- animals. However, SMOX-/- did not prevent progression of kidney injury.

Conclusion

SMOX-/- animals responded with a blunted elevation of circulating acrolein levels after acute and chronic reduced kidney function. Reduction of this uremic toxin did not correlate to improved chronic kidney function in the models assessed here. It remains to be established whether reduction of SMOX activity and acrolein levels have a protective role in other cardiovascular diseases.

Funding

• Commercial Support –