Details

Autor(en) / Beteiligte

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

Titel

Loss of Arhgef11 in the Dahl Salt-Sensitive Rat Protects Against Hypertension-Induced Renal Injury

Ist Teil von

• Hypertension (Dallas, Tex. 1979), 2020-04, Vol.75 (4), p.1012-1024

Ort / Verlag

United States: American Heart Association, Inc

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 SS-Arhgef11-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.