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137 results on '"Johnson, Ashley C."'

1. Sept8/SEPTIN8 involvement in cellular structure and kidney damage is identified by genetic mapping and a novel human tubule hypoxic model

Author

Keele, Gregory R., Prokop, Jeremy W., He, Hong, Holl, Katie, Littrell, John, Deal, Aaron W., Kim, Yunjung, Kyle, Patrick B., Attipoe, Esinam, Johnson, Ashley C., Uhl, Katie L., Sirpilla, Olivia L., Jahanbakhsh, Seyedehameneh, Robinson, Melanie, Levy, Shawn, Valdar, William, Garrett, Michael R., and Solberg Woods, Leah C.

Published
2021
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3. A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models

Author

Zhou, Yiming, Castonguay, Philip, Sidhom, Eriene-Heidi, Clark, Abbe R., Dvela-Levitt, Moran, Kim, Sookyung, Sieber, Jonas, Wieder, Nicolas, Jung, Ji Yong, Andreeva, Svetlana, Reichardt, Jana, Dubois, Frank, Hoffmann, Sigrid C., Basgen, John M., Montesinos, Mónica S., Weins, Astrid, Johnson, Ashley C., Lander, Eric S., Garrett, Michael R., Hopkins, Corey R., and Greka, Anna

Published
2017

17. Nephron-deficient HSRA rats exhibit renal injury with age but have limited renal damage from streptozotocin-induced hyperglycemia.

Author

Cobb, Meredith B., Wenjie Wu, Attipoe, Esinam M., Johnson, Ashley C., and Garrett, Michael R.

Subjects
RATS, DIABETIC nephropathies, HYPERGLYCEMIA, CHRONIC kidney failure, WOUNDS & injuries
Abstract

Hypertension and diabetes are the greatest factors influencing the progression of chronic kidney disease (CKD). Investigation into the role of nephron number in CKD alone or with hypertension has revealed a strong inverse relationship between the two; however, not much is known about the connection between nephron number and diabetic kidney disease. The heterogeneous stock-derived model of unilateral renal agenesis (HSRA) rat, a novel model of nephron deficiency, provides a unique opportunity to study the association between nephron number and hypertension and diabetes on CKD. HSRA rats exhibit failure of one kidney to develop in 50-75% of offspring, whereas the remaining offspring are born with two kidneys. Rats born with one kidney (HSRA-S) develop significant renal injury with age compared with two-kidney littermates (HSRA-C). The induction of hypertension as a secondary stressor leads to significantly more renal injury in HSRA-S compared with HSRA-C rats and nephrectomized HSRA-C (HSRA-UNX) rats. The present study sought to address the hypothesis that nephron deficiency in the HSRA rat would hasten renal injury in the presence of a secondary stressor of hyperglycemia. HSRA animals did not exhibit diabetes-related traits at any age; thus, streptozotocin (STZ) was used to induce hyperglycemia in HSRA-S, HSRA-C, and HSRA-UNX rats. STZand vehicle-treated animals were followed for 15 wk. STZ-treated animals developed robust hyperglycemia, but in contrast to the response to hypertension, neither HSRA-S nor HSRA-UNX animals developed proteinuria compared with vehicle treatment. In total, our data indicate that hyperglycemia from STZ alone does not have a significant impact on the onset or progression of injury in young one-kidney HSRA animals. [ABSTRACT FROM AUTHOR]

Published
2021
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18. Localization and functional consequences of a direct interaction between TRIOBP-1 and hERG proteins in the heart

Author

Jones, David K., Johnson, Ashley C., Roti Roti, Elon C., Liu, Fang, Uelmen, Rebecca, Ayers, Rebecca A., Baczko, Istvan, Tester, David J., Ackerman, Michael J., Trudeau, Matthew C., and Robertson, Gail A.

Subjects
Male, Protein Transport, HEK293 Cells, Transcriptional Regulator ERG, Microfilament Proteins, Animals, Humans, Calcium, Myocytes, Cardiac, Research Article, Protein Binding, Rats
Abstract

Reduced levels of the cardiac human (h)ERG ion channel protein and the corresponding repolarizing current I(Kr) can cause arrhythmia and sudden cardiac death, but the underlying cellular mechanisms controlling hERG surface expression are not well understood. Here, we identified TRIOBP-1, an F-actin-binding protein previously associated with actin polymerization, as a putative hERG-interacting protein in a yeast-two hybrid screen of a cardiac library. We corroborated this interaction by performing Förster resonance energy transfer (FRET) in HEK293 cells and co-immunoprecipitation in HEK293 cells and native cardiac tissue. TRIOBP-1 overexpression reduced hERG surface expression and current density, whereas reducing TRIOBP-1 expression via shRNA knockdown resulted in increased hERG protein levels. Immunolabeling in rat cardiomyocytes showed that native TRIOBP-1 colocalized predominantly with myosin-binding protein C and secondarily with rat ERG. In human stem cell-derived cardiomyocytes, TRIOBP-1 overexpression caused intracellular co-sequestration of hERG signal, reduced native I(Kr) and disrupted action potential repolarization. Ca(2+) currents were also somewhat reduced and cell capacitance was increased. These findings establish that TRIOBP-1 interacts directly with hERG and can affect protein levels, I(Kr) magnitude and cardiac membrane excitability.

Published
2018

27. A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models

Author

Institute for Medical Engineering and Science, Sidhom, Eriene-Heidi I, Lander, Eric Steven, Greka, Anna, Zhou, Yiming, Castonguay, Philip, Clark, Abbe R., Dvela-Levitt, Moran, Kim, Sookyung, Sieber, Jonas, Wieder, Nicolas, Jung, Ji Yong, Andreeva, Svetlana, Reichardt, Jana, Dubois, Frank, Hoffmann, Sigrid C., Basgen, John M., Montesinos, Mónica S., Weins, Astrid, Johnson, Ashley C., Garrett, Michael R., Hopkins, Corey R., Institute for Medical Engineering and Science, Sidhom, Eriene-Heidi I, Lander, Eric Steven, Greka, Anna, Zhou, Yiming, Castonguay, Philip, Clark, Abbe R., Dvela-Levitt, Moran, Kim, Sookyung, Sieber, Jonas, Wieder, Nicolas, Jung, Ji Yong, Andreeva, Svetlana, Reichardt, Jana, Dubois, Frank, Hoffmann, Sigrid C., Basgen, John M., Montesinos, Mónica S., Weins, Astrid, Johnson, Ashley C., Garrett, Michael R., and Hopkins, Corey R.

Abstract

Progressive kidney diseases are often associated with scarring of the kidney’s filtration unit, a condition called focal segmental glomerulosclerosis (FSGS). This scarring is due to loss of podocytes, cells critical for glomerular filtration, and leads to proteinuria and kidney failure. Inherited forms of FSGS are caused by Rac1-activating mutations, and Rac1 induces TRPC5 ion channel activity and cytoskeletal remodeling in podocytes. Whether TRPC5 activity mediates FSGS onset and progression is unknown. We identified a small molecule, AC1903, that specifically blocks TRPC5 channel activity in glomeruli of proteinuric rats. Chronic administration of AC1903 suppressed severe proteinuria and prevented podocyte loss in a transgenic rat model of FSGS. AC1903 also provided therapeutic benefit in a rat model of hypertensive proteinuric kidney disease. These data indicate that TRPC5 activity drives disease and that TRPC5 inhibitors may be valuable for the treatment of progressive kidney diseases., National Institutes of Health (U.S.) (Grant DK095045), National Institutes of Health (U.S.) (Grant DK099465), National Institutes of Health (U.S.) (Grant DK103658), National Institutes of Health (U.S.) (Grant DK083511), National Institutes of Health (U.S.) (Grant DK093746)

Published
2018

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

Author

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

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 SS-Arhgef11SHR-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. [ABSTRACT FROM AUTHOR]

Published
2020
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30. Altered renal hemodynamics is associated with glomerular lipid accumulation in obese Dahl salt-sensitive leptin receptor mutant rats.

Author

McPherson, Kasi C., Shields, Corbin A., Poudel, Bibek, Johnson, Ashley C., Taylor, Lateia, Stubbs, Cassandra, Nichols, Alyssa, Cornelius, Denise C., Garrett, Michael R., and Williams, Jan M.

Subjects
ATP-binding cassette transporters, LEPTIN receptors, HEMODYNAMICS, LIPIDS, GLOMERULAR filtration rate, RATS
Abstract

The present study examined whether development of renal injury in the nondiabetic obese Dahl salt-sensitive leptin receptor mutant (SSLepRmutant) strain is associated with elevations in glomerular filtration rate and renal lipid accumulation. Baseline mean arterial pressure at 6 wk of age was similar between Dahl salt-sensitive wild-type (SSWT) and SSLepRmutant rats. However, by 18 wk of age, the SSLepRmutant strain developed hypertension, while the elevation in mean arterial pressure was not as severe in SSWT rats (192 ± 4 and 149 ± 6 mmHg, respectively). At baseline, proteinuria was fourfold higher in SSLepRmutant than SSWT rats and remained elevated throughout the study. The early development of progressive proteinuria was associated with renal hyperfiltration followed by a decline in renal function over the course of study in the SSLepRmutant compared with SSWT rats. Kidneys from the SSLepRmutant strain displayed more glomerulosclerosis and glomerular lipid accumulation than SSWT rats. Glomeruli were isolated from the renal cortex of both strains at 6 and 18 wk of age, and RNA sequencing was performed to identify genes and pathways driving glomerular injury. We observed significant increases in expression of the influx lipid transporters, chemokine (C-X-C motif) ligand 16 (Cxcl16) and scavenger receptor and fatty acid translocase (Cd36), respectively, and a significant decrease in expression of the efflux lipid transporter, ATP-binding cassette subfamily A member 2 (Abca2; cholesterol efflux regulatory protein 2), in SSLepRmutant compared with SSWT rats at 6 and 18 wk of age, which were validated by RT-PCR analysis. These data suggest an association between glomerular hyperfiltration and glomerular lipid accumulation during the early development of proteinuria associated with obesity. [ABSTRACT FROM AUTHOR]

Published
2020
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39. A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models.

Author

Yiming Zhou, Castonguay, Philip, Sidhom, Eriene-Heidi, Clark, Abbe R., Dvela-Levitt, Moran, Sookyung Kim, Sieber, Jonas, Wieder, Nicolas, Ji Yong Jung, Andreeva, Svetlana, Reichardt, Jana, Dubois, Frank, Hoffmann, Sigrid C., Basgen, John M., Montesinos, Mónica S., Weins, Astrid, Johnson, Ashley C., Lander, Eric S., Garrett, Michael R., and Hopkins, Corey R.

Published
2017
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42. Nephron Deficiency and Predisposition to Renal Injury in a Novel One-Kidney Genetic Model

Author

Wang, Xuexiang, primary, Johnson, Ashley C., additional, Williams, Jan M., additional, White, Tiffani, additional, Chade, Alejandro R., additional, Zhang, Jie, additional, Liu, Ruisheng, additional, Roman, Richard J., additional, Lee, Jonathan W., additional, Kyle, Patrick B., additional, Solberg-Woods, Leah, additional, and Garrett, Michael R., additional

Published
2015
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