Gastric bypass vs. ‘Medical Bypass’ - Impact on experimental diabetic kidney disease

Albuminuria is significantly reduced following Roux-en-Y gastric bypass (RYGB) surgery, suggesting a renoprotective effect of the intervention. Herein, we assess the relative impact of RYGBand RYGB equivalent non-surgical weight loss and glycaemic improvementon glomerularinjury andglobal renal transcriptomic responses in the Zucker diabetic fatty rat (ZDF) model of diabetic nephropathy. We coined the term "medical bypass" (MB) to describe the intensive diet and pharmacotherapy based non-surgical interventionAdult ZDF rats underwent sham surgery (n=15) or RYGB (n=9). Nine sham-operated rats were calorie restricted and received insulin, liraglutide, metformin, ramipril, rosuvastatin and fenofibrate for 2 months (MB). Zucker fa/+ rats acted as healthy controls throughout. Bodyweight, glycaemia, albuminuria and glomerular injury specifically podocyte number, density and ultrastructure were assessed at follow up. Renal transcriptomes were compared by RNA-seq. RYGB resulted in 20-30% weight loss, normalized glycaemia and albuminuria and reduced indices of glomerular injury, specifically podocyte injury (foot process effacement). RYGB equivalent outcomes were obtained on all parameters following MB.白蛋白尿（Albuminuria）在接受Roux-en-Y胃旁路术（Roux-en-Y gastric bypass, RYGB）后显著降低，提示该干预手段具有肾脏保护效应。本研究旨在评估RYGB以及等效于RYGB的非手术减重与血糖改善措施，对糖尿病肾病Zucker糖尿病脂肪大鼠（Zucker diabetic fatty rat, ZDF）模型中的肾小球损伤及全肾脏转录组应答的相对影响。我们将基于强化饮食与药物治疗的非手术干预手段命名为‘药物旁路术（medical bypass, MB）’。成年ZDF大鼠被分为假手术组（n=15）与RYGB组（n=9）；其中9只假手术大鼠接受热量限制，并辅以胰岛素、利拉鲁肽、二甲双胍、雷米普利、瑞舒伐他汀及非诺贝特治疗，干预时长为2个月，该组即为MB组。全程以Zucker fa/+大鼠作为健康对照。随访阶段对大鼠体重、血糖、白蛋白尿以及肾小球损伤指标（具体包括足细胞数量、密度与超微结构）进行了评估。通过RNA测序（RNA-seq）对肾脏转录组进行比较分析。RYGB可使大鼠体重降低20%~30%，血糖与白蛋白尿水平恢复正常，并减轻肾小球损伤相关指标，尤其是足细胞损伤（足突融合）程度。MB干预后，所有观测参数均获得了与RYGB相当的干预效果。