Exploring the role of the metabolite-sensing receptor GPR109a in diabetic nephropathy

Abstract

25Alterations in gut homeostasis may contribute to the progression of diabetic 26 nephropathy. There has been recent attention on the renoprotective effects of 27 metabolite-sensing receptors in chronic renal injury, including the G-protein-coupled-28 receptor (GPR)109a, which ligates the short chain fatty acid butyrate. However, the role 29 of GPR109a in the development of diabetic nephropathy, a milieu of diminished 30 microbiome-derived metabolites, has not yet been determined. This study aimed to 31 assess the effects of insufficient GPR109a signalling via genetic deletion of GPR109a 32 on the development of renal injury in diabetic nephropathy. Gpr109a-/-mice or their 33 wildtype littermates (Gpr109a+/+) were rendered diabetic with streptozotocin (STZ). 34Mice received a control diet or an isocaloric high fiber diet (12.5% resistant starch) for 35 24 weeks and gastrointestinal permeability and renal injury were determined. Diabetes 36 was associated with increased albuminuria, glomerulosclerosis and inflammation. In 37 comparison, Gpr109a-/-mice with diabetes did not show an altered renal phenotype. 38Resistant starch supplementation did not afford protection from renal injury in diabetic 39 nephropathy. Whilst diabetes was associated with alterations in intestinal morphology, 40 intestinal permeability assessed in vivo using the FITC-dextran test was unaltered. 41GPR109a deletion did not worsen gastrointestinal permeability. Further, 12.5% resistant 42 starch supplementation, at physiological concentrations, had no effect on intestinal 43 permeability or morphology. These studies indicate that GPR109a does not play a 44 critical role in intestinal homeostasis in a model of type 1 diabetes or in the development 45 of diabetic nephropathy. 46 47