Diabetes Complications Research Centre, School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland.
Swedish NMR Centre, University of Gothenburg, Gothenburg, Sweden.
Front Endocrinol (Lausanne). 2022 Jan 26;12:757228. doi: 10.3389/fendo.2021.757228. eCollection 2021.
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.
The effects of RYGB and RYGB plus fenofibrate, metformin, ramipril, and rosuvastatin (RYGB-FMRR) on metabolic control and histological and ultrastructural indices of glomerular and proximal tubular injury were compared in the Zucker Diabetic Sprague Dawley (ZDSD) rat model of DKD. Renal cortical transcriptomic (RNA-sequencing) and urinary metabolomic (H-NMR spectroscopy) responses were profiled and integrated. Transcripts were assigned to kidney cell types through deconvolution in kidney single-nucleus RNA-sequencing and microdissected tubular epithelial cell proteomics datasets. Medication-specific transcriptomic responses following RYGB-FMRR were explored using a network pharmacology approach. Omic correlates of improvements in structural and ultrastructural indices of renal injury were defined using a molecular morphometric approach.
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. Fenofibrate was found to be the principal medication effector of gene expression changes following RYGB-FMRR, which led to the transcriptional induction of PPARα-regulated genes that are predominantly expressed in the proximal tubule and which regulate peroxisomal and mitochondrial fatty acid oxidation (FAO). After omics integration, expression of these FAO transcripts positively correlated with urinary levels of PPARα-regulated nicotinamide metabolites and negatively correlated with urinary tricarboxylic acid (TCA) cycle intermediates. Changes in FAO transcripts and nicotinamide and TCA cycle metabolites following RYGB-FMRR correlated strongly with improvements in glomerular and proximal tubular injury.
Integrative multi-omic analyses point to PPARα-stimulated FAO in the proximal tubule as a dominant effector of treatment response to combined surgical and medical therapy in experimental DKD. Synergism between RYGB and pharmacological stimulation of FAO represents a promising combinatorial approach to the treatment of DKD in the setting of obesity.
Roux-en-Y 胃旁路手术（RYGB）可改善糖尿病肾病（DKD）的生化和组织学参数。有针对性的辅助药物治疗可能会增强 RYGB 后的肾脏保护作用。
在 DKD 的 Zucker 糖尿病斯普拉格·道利（ZDSD）大鼠模型中，比较了 RYGB 和 RYGB 加非诺贝特、二甲双胍、雷米普利和罗苏伐他汀（RYGB-FMRR）对代谢控制以及肾小球和近端肾小管损伤的组织学和超微结构指标的影响。通过肾脏单核 RNA 测序和微分离管状上皮细胞蛋白质组学数据集对肾脏皮质转录组（RNA-seq）和尿液代谢组（H-NMR 光谱）反应进行了分析和整合。通过去卷积将转录本分配到肾脏细胞类型中。使用网络药理学方法探索 RYGB-FMRR 后的药物特异性转录组反应。使用分子形态计量学方法定义改善肾脏损伤的结构和超微结构指标的组学相关性。
RYGB-FMRR 在代谢控制、白蛋白尿和肾小球损伤的组织学和超微结构指标方面优于 RYGB 单独治疗。RYGB-FMRR 比 RYGB 更能逆转近端肾小管中线粒体形态的 DKD 相关变化。RYGB-FMRR 后，促纤维化反应的转录途径水平激活的减弱程度大于 RYGB。RYGB-FMRR 后，发现非诺贝特是药物治疗后基因表达变化的主要药物效应子，这导致了 PPARα 调节的基因的转录诱导，这些基因主要在近端肾小管中表达，并调节过氧化物酶体和线粒体脂肪酸氧化（FAO）。进行组学整合后，这些 FAO 转录物的表达与尿中 PPARα 调节的烟酰胺代谢物水平呈正相关，与尿中三羧酸（TCA）循环中间产物呈负相关。RYGB-FMRR 后 FAO 转录物和烟酰胺及 TCA 循环代谢物的变化与肾小球和近端肾小管损伤的改善密切相关。
综合多组学分析表明，近端肾小管中的 PPARα 刺激的 FAO 是肥胖背景下实验性 DKD 联合手术和药物治疗反应的主要效应因子。RYGB 与 FAO 的药理学刺激之间的协同作用代表了治疗 DKD 的一种很有前途的组合方法。
