Kidney Week

Abstract: TH-PO205

Lipoxins Protect Against Diabetic Kidney Disease by Attenuating the Expression of Inflammatory Genes

Session Information

• Diabetic Kidney Disease: Basic - I
  November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Kantharidis, Phillip, Monash University Department of Diabetes, Melbourne, Victoria, Australia

Phillip Kantharidis,

• Bose, Madhura, Monash University Department of Diabetes, Melbourne, Victoria, Australia

Madhura Bose,

• Priori, Victoria, Ecole de Biologie Industrielle, Cergy, Île-de-France, France

Victoria Priori,

• Mohan, Muthukumar, Monash University Department of Diabetes, Melbourne, Victoria, Australia

Muthukumar Mohan,

• Brennan, Eoin, School of Medicine and Conway Institute, University College Dublin, Dublin, Ireland

Eoin Brennan,

• Godson, Catherine, School of Medicine and Conway Institute, University College Dublin, Dublin, Ireland

Catherine Godson,

• Cooper, Mark E., Monash University Department of Diabetes, Melbourne, Victoria, Australia

Mark E. Cooper,

Background

Many factors contribute to the pathology observed in diabetic kidney disease (DKD) with chronic hyperglycaemia driving the increased generation of ROS and AGEs, ultimately leading to inflammation and kidney fibrosis. In recent years, there has been growing appreciation that the failure of effective resolution of inflammation may underpin DKD. In this context the efficacy of lipoxins [LXs], lipid mediators that promote the resolution of inflammation and suppress fibrosis has been proposed. Here we examined the efficacy of LXs and novel synthetic LX mimetics in experimental DKD compared to candesartan, the current standard of care.

Methods

Six-week-old male ApoE KO mice were rendered diabetic by five daily intra-peritoneal (IP) injections of streptozotocin (55mg/kg). Blood glucose and HbA1c were measured to determine diabetes status. Control and diabetic mice were randomly selected to receive vehicle (0.02% ethanol), LXA₄ (5μg/kg), or two mimetics, AT-02-CT (1.7μg/kg) or AT-01-KG (3μg/kg) via IP (n=24/gp), twice weekly. At endpoint, mice were culled and kidneys collected for gene expression, immunohistochemistry and histology.

Results

Diabetic mice displayed elevated blood glucose, HbA1c and albuminuria compared to control. These changes were accompanied with significantly increased fibrotic (fibronectin, Col 1), inflammatory (TNFα, MCP1, IL-6) and adhesion markers (VCAM-1, ICAM-1). Administration of candesartan, LXA4 or the mimetics significantly reduced inflammatory and adhesion marker expression in diabetic kidney. LXA₄ and the mimetics also resulted in significantly decreased albuminuria (~40%) and reduced mesangial expansion. LXA₄ and the mimetics were equally effective against fibronectin, collagen 1 and inflammatory markers compared to candesartan alone. However, when compared to the combination treatment with candesartan, Lipoxins alone provide superior protection.

Conclusion

Our findings demonstrated that LX and synthetic LX mimetics protect against DKD by attenuating fibrotic and inflammatory signalling and improving kidney function. For some parameters, Lipoxins provided superior protection compared to candesartan, including the combination treatments with candesartan. These results support the use of Lipoxins as a novel pro-resolving approach for the treatment of DKD.

Funding

• Government Support – Non-U.S.