Comparative RNA-Seq transcriptome analyses reveal distinct metabolic pathways in diabetic nerve and kidney disease.
Comparative RNA-Seq transcriptome analyses reveal distinct metabolic pathways in diabetic nerve and kidney disease.
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比较RNA-SEQ转录组分析揭示了糖尿病神经和肾脏疾病的不同代谢途径。
DOI：
10.1111/jcmm.13136
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发表时间：
2017-09
影响因子：
5.3
通讯作者：
Feldman EL
中科院分区：
文献类型：
--
作者：
Hinder LM;Park M;Rumora AE;Hur J;Eichinger F;Pennathur S;Kretzler M;Brosius FC 3rd;Feldman EL
用吡格列酮治疗胰岛素抵抗可使肾功能正常化，并改善小神经纤维功能和结构;然而，在2型糖尿病（T2 DM）小鼠模型中，它不影响大的有髓鞘神经纤维功能，表明吡格列酮以组织特异性方式影响身体。为了确定调节糖尿病周围神经病变（DPN）和肾病（DN）的不同分子途径，以及吡格列酮影响的分子途径，我们评估了对照组和糖尿病小鼠（有或无吡格列酮治疗）中DPN和DN基因转录本的表达。然后并行使用差异表达分析和自组织图谱来分析转录组数据。差异表达分析表明，促进细胞死亡和炎症反应的基因表达在肾小球逆转，但不变或加剧坐骨神经吡格列酮。自组织图谱分析显示，通过治疗，肾脏和神经中的线粒体功能障碍正常化;然而，保守途径的调节方向相反。总的来说，我们的数据表明炎症可能导致大纤维功能障碍，而线粒体功能障碍可能导致T2 DM中的小纤维功能障碍。此外，靶向这两种途径可能会改善DN。这项研究支持越来越多的证据表明，T2 DM的全身代谢变化与肾脏和神经中不同的组织特异性代谢重编程相关，并且这些变化在DN和小纤维DPN发病机制中起关键作用。这些数据还强调了T2 DM治疗方法“一刀切”的潜在危险，因为同一种药物可能同时缓解一种并发症，同时加剧另一种并发症。
Treating insulin resistance with pioglitazone normalizes renal function and improves small nerve fibre function and architecture; however, it does not affect large myelinated nerve fibre function in mouse models of type 2 diabetes (T2DM), indicating that pioglitazone affects the body in a tissue‐specific manner. To identify distinct molecular pathways regulating diabetic peripheral neuropathy (DPN) and nephropathy (DN), as well those affected by pioglitazone, we assessed DPN and DN gene transcript expression in control and diabetic mice with or without pioglitazone treatment. Differential expression analysis and self‐organizing maps were then used in parallel to analyse transcriptome data. Differential expression analysis showed that gene expression promoting cell death and the inflammatory response was reversed in the kidney glomeruli but unchanged or exacerbated in sciatic nerve by pioglitazone. Self‐organizing map analysis revealed that mitochondrial dysfunction was normalized in kidney and nerve by treatment; however, conserved pathways were opposite in their directionality of regulation. Collectively, our data suggest inflammation may drive large fibre dysfunction, while mitochondrial dysfunction may drive small fibre dysfunction in T2DM. Moreover, targeting both of these pathways is likely to improve DN. This study supports growing evidence that systemic metabolic changes in T2DM are associated with distinct tissue‐specific metabolic reprogramming in kidney and nerve and that these changes play a critical role in DN and small fibre DPN pathogenesis. These data also highlight the potential dangers of a ‘one size fits all’ approach to T2DM therapeutics, as the same drug may simultaneously alleviate one complication while exacerbating another.
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DOI：
10.1002/art.38679
发表时间：
2014-08
期刊：
Arthritis & rheumatology (Hoboken, N.J.)
影响因子：
--
作者：
Bethunaickan R;Berthier CC;Zhang W;Eksi R;Li HD;Guan Y;Kretzler M;Davidson A
通讯作者：
Davidson A
DOI：
10.1530/joe-12-0356
发表时间：
2013-01
期刊：
The Journal of endocrinology
影响因子：
--
作者：
Hinder LM;Vivekanandan-Giri A;McLean LL;Pennathur S;Feldman EL
通讯作者：
Feldman EL
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
4.8
作者：
Jiang, Youde;Thakran, Shalini;Steinle, Jena J.
通讯作者：
Steinle, Jena J.
影响因子：
3.2
作者：
Deshpande, Anjali D.;Harris-Hayes, Marcie;Schootman, Mario
通讯作者：
Schootman, Mario