Loss of Arhgef11 in the Dahl Salt-Sensitive Rat Protects Against Hypertension-Induced Renal Injury
| Autor: | Kurt C. Showmaker, Erin B. Taylor, Ashley C. Johnson, Patrick B. Kyle, Jennifer M. Sasser, Wenjie Wu, Esinam M. Attipoe, Merry L. Lindsey, Michael R. Garrett |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Blood Pressure 030204 cardiovascular system & hematology Kidney Article Nucleotide exchange factor 03 medical and health sciences 0302 clinical medicine Renal injury Fibrosis Internal medicine Internal Medicine medicine Kidney injury Animals Guanine Nucleotide Exchange Factors Renal Insufficiency Chronic Dahl salt sensitive Proteinuria Rats Inbred Dahl business.industry medicine.disease Rats 030104 developmental biology Endocrinology Blood pressure Hypertension medicine.symptom business Kidney disease |
| Zdroj: | Hypertension |
| Popis: | 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 SHR -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. |
| Databáze: | OpenAIRE |
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