ABSTRACT Introduction Roux-en-Y Gastric Bypass Surgery (RYGB) reduces albuminuria and the long-term incidence of end-stage renal disease in patients with obesity and diabetes. Preclinical modelling in experimental diabetic kidney disease (DKD) demonstrates that improvements in glomerular structure likely underpin these findings. Research Design &amp; Methods In adult male Zucker Diabetic Fatty (ZDF) rats, we profiled the effect of RYGB on weight and metabolic control as well biochemical, structural and ultrastructural indices of diabetic renal injury. Furthermore, we sequenced the renal cortical transcriptome in these rats and used bioinformatic pathway analyses to characterise the transcriptional alterations governing the renal reparative response to RYGB Results In parallel with improvements in weight and metabolic control, RYGB reduced albuminuria, glomerulomegaly, podocyte stress, and podocyte foot process effacement. Pathway analysis of RYGB-induced transcriptomic changes in the renal cortex highlighted correction of disease-associated alterations in fibrosis, inflammation and biological oxidation pathways. RYGB reversed disease-associated changes in the expression of TGF-β superfamily genes that strongly correlated with improvements in structural measures of glomerulopathy. Conclusions Improved glomerular structure in ZDF rats following RYGB is underpinned by pathway level changes, including interruption of the TGF-β driven pro-fibrotic programme. Our data provide an important layer of experimental support for clinical evidence demonstrating that RYGB arrests renal damage in patients with obesity and Type 2 Diabetes. KEY MESSAGES What is already known about this subject? RYGB is an effective treatment for obesity and type 2 diabetes and longitudinal cohort studies have demonstrated it’s albuminuria lowering effect and evidence of longer term reno-protection. Studies in pre-clinical models of diabetic kidney disease have described favourable changes in measures of renal structure and ultrastructure following RYGB. What are the new findings? The present study directly correlates structural and ultrastructural improvements in the ZDF rat kidney following RYGB with corrective shifts in the global renal transcriptome. Chronic renal remodelling responses in experimental DKD that are governed by TGF-β signalling are interrupted and reversed by RYGB. How might these results change the focus of research or clinical practice? These data will support further interrogation of RYGB specific shifts in the renal transcriptome with a view to identifying tractable targets for treatment response biomarkers and bariatric mimetic based diet and pharmacotherapy based interventions.

Characterisation of the Renal Cortical Transcriptome Following Roux-en-Y Gastric Bypass Surgery in Experimental Diabetic Kidney Disease