Abstract
Previously, genetic analyses identified that variants in Arhgef11 may influence kidney injury in the Dahl salt-sensitive (S) rat, a model of hypertensive chronic kidney disease. To understand the potential mechanism by which altered expression and/or protein differences in Arhgef11 could play a role in kidney injury, stably transduced Arhgef11 knockdown cell lines as well as primary cultures of proximal tubule cells were studied. Genetic knockdown of Arhgef11 in HEK293 and NRK resulted in reduced RhoA activity, decreased activation of Rho-ROCK pathway, and less stress fiber formation versus control, similar to what was observed by pharmacological inhibition (fasudil). Primary proximal tubule cells (PTC) cultured from the S exhibited increased expression of Arhgef11, increased RhoA activity, and up regulation of Rho-ROCK signaling compared to control (small congenic). The cells were also more prone (versus control) to TGFβ-1 induced epithelial-mesenchymal transition (EMT), a hallmark feature of the development of renal interstitial fibrosis, and characterized by development of spindle shape morphology, gene expression changes in EMT markers (Col1a3, Mmp9, Bmp7, and Ocln) and increased expression of N-Cadherin and Vimentin. S derived PTC demonstrated a decreased ability to uptake FITC-albumin compared to the small congenic in vitro, which was confirmed by assessment of albumin re-uptake in vivo by infusion of FITC-albumin and immunofluorescence imaging. In summary, these studies suggest that genetic variants in the S form of Arhgef11 via increased expression and/or protein activity play a role in promoting kidney injury in the S rat through changes in cell morphology (Rho-Rock and/or EMT) that impact the function of tubule cells.
Highlights
Chronic kidney disease (CKD) is seen in all age groups and impacts an estimated 20–30 million people in the United States alone, with hypertension being a major risk factor [1]
Arhgef11, a Rho guanine nucleotide exchange factor was previously implicated in kidney injury and reduced function exhibited by the Dahl salt-sensitive (S) rat, a model of hypertensive related chronic kidney disease (CKD) [9, 12]
An extensive characterization of an Arhgef11-congenic strain suggested that the most likely physiological mechanism associated with Arhgef11 was tubular mediated as glomerular permeability (Palb) and glomerular injury was similar between the two strains [9]
Summary
Chronic kidney disease (CKD) is seen in all age groups and impacts an estimated 20–30 million people in the United States alone, with hypertension being a major risk factor [1] Those with CKD initially demonstrate some sign of kidney injury (e.g., proteinuria), but as kidney injury worsens there can be a significant decline in kidney function, leading to an increased risk for renal failure as well as other cardiovascular diseases [2]. Aside from the economic impact, current treatment options are not ideal and only serve to slow the progression of CKD These factors underscore the importance of identifying genes, pathways and genetic interactions involved in hypertensive related CKD, which could be integral in the development of diagnostic tools and therapeutic targets for prevention and treatment. A number of gene-gene interactions have been identified that demonstrated an epistatic effect on kidney injury [13]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
