Kidney Week

Abstract: PO0700

Medications Targeting the Activation of Tubular Fatty Acid Oxidation Enhance the Renoprotective Effects of Roux-en-Y Gastric Bypass Surgery

Session Information

• Diabetic Kidney Disease: Basic - II
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Martin, William P., Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland

William P. Martin,

• Chuah, Yeong Huei Desmond, Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland

Yeong Huei Desmond Chuah,

• Abdelaal, Mahmoud, Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland

Mahmoud Abdelaal,

• Pedersen, Anders, Goteborgs Universitet, Goteborg, Västra Götaland, Sweden

Anders Pedersen,

• Malmodin, Daniel, Goteborgs Universitet, Goteborg, Västra Götaland, Sweden

Daniel Malmodin,

• Abrahamsson, Sanna, Goteborgs Universitet, Goteborg, Västra Götaland, Sweden

Sanna Abrahamsson,

• Hutter, Michaela, Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland

Michaela Hutter,

• Godson, Catherine, Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland

Catherine Godson,

• Brennan, Eoin, Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland

Eoin Brennan,

• Fandriks, Lars, Goteborgs Universitet, Goteborg, Västra Götaland, Sweden

Lars Fandriks,

• Le roux, Carel W., Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland

Carel W. Le roux,

• Docherty, Neil G., Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland

Neil G. Docherty,

Background

Roux-en-Y gastric bypass surgery (RYGB) improves biochemical and histological parameters of diabetic kidney disease (DKD). Targeted adjunct medical therapy may enhance renoprotection following RYGB.

Methods

The effects of RYGB (n=10) and RYGB plus fenofibrate 100mg/kg, metformin 300mg/kg, ramipril 1mg/kg, and rosuvastatin 10mg/kg (RYGB-FMRR; n=9) on metabolic control and histological and ultrastructural indices of renal injury were compared after 8 weeks of treatment in the Zucker Diabetic Sprague Dawley (ZDSD) rat model of DKD. Sham-operated ZDSD rats (n=9) and healthy Sprague Dawley rats (n=6) served as controls. Renal cortical transcriptomic (RNA-sequencing) and urinary metabolomic (¹H-NMR spectroscopy) responses were profiled and integrated. Omic correlates of improvements in structural and ultrastructural indices of renal injury were defined using a molecular morphometric approach.

Results

RYGB-FMRR was superior to RYGB alone with respect to metabolic control, albuminuria, and histological and ultrastructural indices of glomerular injury. RYGB-FMRR reversed DKD-associated changes in mitochondrial morphology in the proximal tubule to a greater extent than RYGB. Attenuation of transcriptomic pathway level activation of pro-fibrotic responses was greater after RYGB-FMRR than RYGB. Transcriptional induction of PPARα-regulated genes, expressed in the proximal tubule and governing fatty acid oxidation (FAO), was a unique feature of the RYGB-FMRR transcriptome associated with increased urinary PPARα-responsive nicotinamide metabolites and reduced urinary tricarboxylic acid (TCA) cycle intermediates. Multi-omic integration identified a strongly positively correlated network of FAO transcripts and nicotinamide metabolites as being distinctive to RYGB-FMRR. Changes in FAO transcripts, nicotinamide metabolites, and TCA cycle intermediates correlated strongly with improvements in glomerular and proximal tubular injury following RYGB-FMRR.

Conclusion

The renoprotective effects of RYGB can be enhanced through the deployment of medications targeting PPARα-mediated activation of tubular FAO responses.

Funding

• Government Support – Non-U.S.