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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 modeling in experimental diabetic kidney disease demonstrates that improvements in glomerular structure likely underpin these findings.
Research design and 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 characterize 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 transforming growth factor (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 early profibrotic 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.
- bariatric surgery
- kidney/glomerulus/pathology
- RNA studies
- ZDF rat(s)
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Footnotes
Contributors NGD, LF and CWlR devised and designed the studies. MN, JAE, NF, HE and NGD performed surgery and animal husbandry. MN conducted biochemical assays, RNA-Seq, histological and immunohistochemical studies with support from HE, JMcC and WPM. Bioinformatic pathway and upstream regulator analyses were conducted by WPM, VZ and EPB. Validation of transcriptomic signals at mRNA and protein level was conducted by MN, MM and WPM. NGD, MN, WPM, EPB, LF, CG and CWlR analyzed and interpreted data. NGD, WPM, MN and CWlR drafted the manuscript with critical input from CG, EPB and LF.
Funding Funding support from the following agencies is acknowledged: Science Foundation Ireland (12/YI/B2480) to ClR, Swedish Medical Research Council (2015-02733) and European Foundation for the Study of Diabetes /Boehringer Ingelheim European Diabetes Research Programme (BI 2017_3) to ClR and NGD, Science Foundation Ireland (15/IA/3152 and 15/US/B3130) to CG and EPB. WPM’s contribution was performed within the Irish Clinical Academic Training (ICAT) Programme, supported by the Wellcome Trust and the Health Research Board (Grant Number 203930/B/16/Z), the Health Service Executive National Doctors Training and Planning and the Health and Social Care, Research and Development Division, Northern Ireland.
Competing interests CWlR discloses personal fees outside of the submitted work from Novo Nordisk, GI Dynamics, Eli Lilly, Johnson and Johnson, Sanofi, Aventis, AstraZeneca, Janssen, Bristol-Myers Squibb and Boehringer-Ingelheim. NGD and CWlR are co-guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Patient consent for publication Not required.
Ethics approval All studies detailed were approved by the University College Dublin Animal Research Ethics Committee and licensed by Government of Ireland Health Products Regulatory Agency (protocol #AE18692-P084).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement RNA-Seq data are deposited at GEO as per Methods section of the manuscript (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE117380). All other data are available on reasonable request from the corresponding author Dr Neil Docherty: neil.docherty@ucd.ie.