Loss of ARHGEF11 in the Dahl salt-sensitive rat protects against hypertension-induced renal injury

Ashley C. Johnson, Wenjie Wu, Esinam M. Attipoe, Jennifer M. Sasser, Erin B. Taylor, Kurt C. Showmaker, Patrick B. Kyle, Merry L. Lindsey, Michael R. Garrett

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

—Arhgef11 is a Rho-guanine nucleotide exchange factor that was previously implicated in kidney injury in the Dahl salt-sensitive (SS) rat, a model of hypertension-related chronic kidney disease. Reduced Arhgef11 expression in an SSArhgef11SHR-minimal congenic strain (spontaneously hypertensive rat allele substituted for S allele) significantly decreased proteinuria, fibrosis, and improved renal hemodynamics, without impacting blood pressure compared with the control SS (SS-wild type). Here, SS-Arhgef11−/− and SS-wild type rats were placed on either low or elevated salt (0.3% or 2% NaCl) from 4 to 12 weeks of age. On low salt, starting at week 6 and through week 12, SS-Arhgef11−/− animals demonstrated a 3-fold decrease in proteinuria compared with SS-wild type. On high salt, beginning at week 6, SS-Arhgef11−/− animals demonstrated >2-fold lower proteinuria from weeks 8 to 12 and 30 mm Hg lower BP compared with SS-wild type. To better understand the molecular mechanisms of the renal protection from loss of Arhgef11, both RNA sequencing and discovery proteomics were performed on kidneys from week 4 (before onset of renal injury/proteinuria between groups) and at week 12 (low salt). The omics data sets revealed loss of Arhgef11 (SS-Arhgef11−/−) initiates early transcriptome/ protein changes in the cytoskeleton starting as early as week 4 that impact a number of cellular functions, including actin cytoskeletal regulation, mitochondrial metabolism, and solute carrier transporters. In summary, in vivo phenotyping coupled with a multi-omics approach provides strong evidence that increased Arhgef11 expression in the Dahl SS rat leads to actin cytoskeleton-mediated changes in cell morphology and cell function that promote kidney injury, hypertension, and decline in kidney function.

Original languageEnglish (US)
Pages (from-to)1012-1024
Number of pages13
JournalHypertension
DOIs
StatePublished - Apr 1 2020

Keywords

  • Alleles
  • Blood pressure
  • Cytoskeleton
  • Fibrosis
  • Proteinuria

ASJC Scopus subject areas

  • Internal Medicine

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    Johnson, A. C., Wu, W., Attipoe, E. M., Sasser, J. M., Taylor, E. B., Showmaker, K. C., Kyle, P. B., Lindsey, M. L., & Garrett, M. R. (2020). Loss of ARHGEF11 in the Dahl salt-sensitive rat protects against hypertension-induced renal injury. Hypertension, 1012-1024. https://doi.org/10.1161/HYPERTENSIONAHA.119.14338