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Abstract: TH-PO213

miR-34a as a Potential Marker in Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Karihaloo, Anil K., Novo Nordisk AS, Seattle, Washington, United States
  • Das, Vivek, Novo Nordisk AS, Seattle, Washington, United States
  • Liu, Shuya, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Ju, Wenjun, University of Michigan Medical School, Ann Arbor, Michigan, United States
  • Nair, Viji, University of Michigan Medical School, Ann Arbor, Michigan, United States
  • Goea, Laura, Bayer CropScience AG, Monheim, Nordrhein-Westfalen, Germany
  • Bitzer, Markus, University of Michigan Medical School, Ann Arbor, Michigan, United States
  • O'Connor, Christopher Lund, Swiss Institute of Bioinformatics, Lausanne, Vaud, Switzerland
  • Kretzler, Matthias, University of Michigan Medical School, Ann Arbor, Michigan, United States
  • Huber, Tobias B., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
Background

Diabetic kidney disease (DKD) is the most common complication of diabetes. Various rodent models recapitulate human DKD only partially. Literature evidence suggests role of short non-coding microRNAs in DKD [1]. Through BEAt-DKD we have interrogated the transcriptional and post-transcriptional networks associated with DKD in BTBR Ob/Ob [2] mice in a multi-parametric design spanning across Genotype, Sex differences and course of the disease trajectory.

Methods

NanoString microRNA panel (n = 600) was used to profile 200 samples comprising of kidney, urine and serum. We used NACHO for quality control, quantification and limma for multivariable regression to identify microRNAs associating with the phenotypic differences between Ob/Ob vs WT, male vs female, and correlated with disease progression. Quantitative imaging assessment was used to identify kidney phenotypic differences in Ob/Ob vs WT. A support vector machines (SVMs)-based tool miRDB was used to predict functional microRNA-gene targets that are conserved between mice and human with confidence score ≥ 60 and significantly changed in DKD.

Results

miR-34a emerged as one of the strongest candidates up-regulated in Ob/Ob kidney and urine (adj.p-value < 0.05). miRDB identified 20 gene targets of miR-34a that are conserved between mice and human, differentially regulated (adj.p-value < 0.05) in human DKD Glomerular RNASeq data and mouse DKD bulk RNASeq data. These miR-34a gene targets included AMAD12, AXL, PDGFRA. PROM-1, etc that enriched for pathways involved in DKD pathogenesis like cell adhesion, podocyte injury, hypoxia inducible factor (HIF)/vascular endothelial growth factor signalling.

Conclusion

Our integrative analysis, identified miR-34a and its conserved gene targets significantly changed in both DKD mice and human datasets, revealed molecular networks and pathways with underlying association with disease, thus indicating its potential role in DKD.

References:
1. Loganathan TS, Sulaiman SA, Abdul Murad NA, et al. Interactions Among Non-Coding RNAs in Diabetic Nephropathy. Front Pharmacol. 2020;11:191. Published 2020 Mar 3. doi:10.3389/fphar.2020.00191
2. Hudkins, Kelly L et al. “BTBR Ob/Ob mutant mice model progressive diabetic nephropathy.” Journal of the American Society of Nephrology: JASN vol. 21,9 (2010): 1533-42. doi:10.1681/ASN.2009121290

Funding

  • Government Support – Non-U.S.