ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: PO1982

Systematic In Silico Exploration of the Kidney Rho-GTPase System Regulation in CKD

Session Information

  • Podocyte Biology
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Reznichenko, Anna, AstraZeneca R&D, Gothenburg, Sweden
  • Buvall, Lisa, AstraZeneca R&D, Gothenburg, Sweden
Background

It has become evident that dysregulation of the RhoGTPase system would result in rearrangement of the actin cytoskeleton in the podocyte with resulting foot process effacement, a hallmark for glomerular diseases. To build further understanding how this disbalance in the RhoGTPase system occurs in CKD, we performed a systematic mining of kidney transcriptomics data to generate a full-picture view and insights on complex interplay between the members of the large family of RhoGTPases and their regulatory proteins, the Guanine Nucleotide Exchange Factors (GEFs) and the GTPase-activating proteins (GAPs).

Methods

A comprehensive list of 143 genes was compiled including the members of the three gene families according to HUGO Gene Nomenclature Committee (HGNC). Publicly available human transcriptomics data from healthy and CKD kidneys (microarray and RNA-seq, bulk-tissue and single-cell) were used for interrogation of gene expression patterns, including presence of detectable expression, its abundance, cell type specificity, modulation in disease, and co-expression structure. WGCNA and Cytoscape were used to correspondingly generate and visualize the gene co-expression network.

Results

All but one (142/143) genes were detectable in the human kidney, with 121 having robust levels >1TPM. The majority of genes were broadly expressed across the different tissues outside the kidney, however expression of several GEF and GAP members showed specific kidney enrichment. A number of GEFs and GAPs were modulated in CKD patient kidneys as compared to controls, predominantly with tendency for up-regulation and negative correlation with renal function, reflecting modulation in potentially pathophysiological or compensatory disease mechanisms. Hierarchical clustering of pairwise correlation values and WGCNA module analyses identified clusters of similarly expressed genes that may implicate functional similarities.

Conclusion

To our knowledge, this is the first systematic evaluation of the RhoGTPases, GEFs and GAPs kidney expression in the CKD context. Elucidation of the molecular interplay provides systems-level understanding and mechanistic insights that can lead to new biological hypotheses and therapeutic targets.

Funding

  • Commercial Support