A molecular morphometric approach to diabetic kidney disease can link structure to function and outcome.
A molecular morphometric approach to diabetic kidney disease can link structure to function and outcome.
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DOI：
10.1016/j.kint.2017.08.013
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发表时间：
2018-03
影响因子：
19.6
通讯作者：
Kretzler M
中科院分区：
文献类型：
--
作者：
Nair V;Komorowsky CV;Weil EJ;Yee B;Hodgin J;Harder JL;Godfrey B;Ju W;Boustany-Kari CM;Schwarz M;Lemley KV;Nelson PJ;Nelson RG;Kretzler M
糖尿病肾病是导致肾衰竭的主要原因。然而，早期肾损伤的分子机制的研究是缺乏的。在这里，我们研究了在皮马印第安人2型糖尿病的早期糖尿病肾病的转录调控和定量结构损伤之间可能存在的联系。从方案肾活检获得的组织进行全基因组特异性基因表达谱和定量形态学分析。与转录调控最密切相关的超微结构病变是皮质间质体积分数（VvInt），这是肾小管间质损伤的指标。转录共表达网络分析确定了1843个与VvInt显著相关的转录本。这些转录本富含与线粒体功能障碍、炎症、迁移机制和肾小管代谢功能相关的途径。通路网络分析确定IL-1β是炎症反应的关键上游调节因子，并且5种转录因子与p53合作调节代谢功能。VvInt-associated transcripts显示与尿白蛋白/肌酐比值和活检后10年测量的肾小球滤过率显著相关，建立了早期分子事件与长期疾病进展之间的联系。因此，通过将肾内转录本与定量形态测量学和长期结果相关联，揭示了糖尿病肾病早期活跃的分子机制。这为识别早期糖尿病肾病急需的治疗靶点和非侵入性生物标志物提供了起点。
Diabetic kidney disease is the leading cause of kidney failure. However, studies of molecular mechanisms of early kidney damage are lacking. Here we examined for possible linkage between transcriptional regulation and quantitative structural damage in early diabetic kidney disease in Pima Indians with type 2 diabetes. Tissue obtained from protocol kidney biopsies underwent genome-wide compartment-specific gene expression profiling and quantitative morphometric analysis. The ultrastructural lesion most strongly associated with transcriptional regulation was cortical interstitial fractional volume (VvInt), an index of tubule-interstitial damage. Transcriptional co-expression network analysis identified 1843 transcripts that correlated significantly with VvInt. These transcripts were enriched for pathways associated with mitochondrial dysfunction, inflammation, migratory mechanisms, and tubular metabolic functions. Pathway network analysis identified IL-1β as a key upstream regulator of the inflammatory response and five transcription factors cooperating with p53 to regulate metabolic functions. VvInt-associated transcripts showed significant correlation with the urine albumin to creatinine ratio and measured glomerular filtration rate 10 years after biopsy, establishing a link between the early molecular events and long-term disease progression. Thus, molecular mechanisms active early in diabetic kidney disease were revealed by correlating intrarenal transcripts with quantitative morphometry and long-term outcomes. This provides a starting point for identification of urgently needed therapeutic targets and non-invasive biomarkers of early diabetic kidney disease.
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WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
影响因子：
120.7
作者：
de Boer, Ian H.;Rue, Tessa C.;Hall, Yoshio N.;Heagerty, Patrick J.;Weiss, Noel S.;Himmelfarb, Jonathan
通讯作者：
Himmelfarb, Jonathan
影响因子：
2.6
作者：
Neuhofer W
通讯作者：
Neuhofer W
影响因子：
8.2
作者：
Brosius FC;Tuttle KR;Kretzler M
通讯作者：
Kretzler M
影响因子：
13.2
作者：
Collins, Allan J.;Foley, Robert N.;Agodoa, Lawrence
通讯作者：
Agodoa, Lawrence