Browsing by Author "Kirkbride-Romeo, Lara"

Now showing 1 - 6 of 6
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    Acute Kidney Injury Results in Long-Term Diastolic Dysfunction That Is Prevented by Histone Deacetylase Inhibition
    (Elsevier, 2021-02-22) Soranno, Danielle E.; Kirkbride-Romeo, Lara; Wennersten, Sara A.; Ding, Kathy; Cavasin, Maria A.; Baker, Peter; Altmann, Christopher; Bagchi, Rushita A.; Haefner, Korey R.; Steinkühler, Christian; Montford, John R.; Keith, Brysen; Gist, Katja M.; McKinsey, Timothy A.; Faubel, Sarah; Pediatrics, School of Medicine
    Growing epidemiological data demonstrate that acute kidney injury (AKI) is associated with long-term cardiovascular morbidity and mortality. Here, the authors present a 1-year study of cardiorenal outcomes following bilateral ischemia-reperfusion injury in male mice. These data suggest that AKI causes long-term dysfunction in the cardiac metabolome, which is associated with diastolic dysfunction and hypertension. Mice treated with the histone deacetylase inhibitor, ITF2357, had preservation of cardiac function and remained normotensive throughout the study. ITF2357 did not protect against the development of kidney fibrosis after AKI.
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    Female and male mice have differential longterm cardiorenal outcomes following a matched degree of ischemia–reperfusion acute kidney injury
    (Springer Nature, 2022-01-12) Soranno, Danielle E.; Baker, Peter, II.; Kirkbride-Romeo, Lara; Wennersten, Sara A.; Ding, Kathy; Keith, Brysen; Cavasin, Maria A.; Altmann, Christopher; Bagchi, Rushita A.; Haefner, Korey R.; Montford, John; Gist, Katja M.; Vergnes, Laurent; Reue, Karen; He, Zhibin; Elajaili, Hanan; Okamura, Kayo; Nozik, Eva; McKinsey, Timothy A.; Faubel, Sarah; Pediatrics, School of Medicine
    Acute kidney injury (AKI) is common in patients, causes systemic sequelae, and predisposes patients to long-term cardiovascular disease. To date, studies of the effects of AKI on cardiovascular outcomes have only been performed in male mice. We recently demonstrated that male mice developed diastolic dysfunction, hypertension and reduced cardiac ATP levels versus sham 1 year after AKI. The effects of female sex on long-term cardiac outcomes after AKI are unknown. Therefore, we examined the 1-year cardiorenal outcomes following a single episode of bilateral renal ischemia–reperfusion injury in female C57BL/6 mice using a model with similar severity of AKI and performed concomitantly to recently published male cohorts. To match the severity of AKI between male and female mice, females received 34 min of ischemia time compared to 25 min in males. Serial renal function, echocardiograms and blood pressure assessments were performed throughout the 1-year study. Renal histology, and cardiac and plasma metabolomics and mitochondrial function in the heart and kidney were evaluated at 1 year. Measured glomerular filtration rates (GFR) were similar between male and female mice throughout the 1-year study period. One year after AKI, female mice had preserved diastolic function, normal blood pressure, and preserved levels of cardiac ATP. Compared to males, females demonstrated pathway enrichment in arginine metabolism and amino acid related energy production in both the heart and plasma, and glutathione in the plasma. Cardiac mitochondrial respiration in Complex I of the electron transport chain demonstrated improved mitochondrial function in females compared to males, regardless of AKI or sham. This is the first study to examine the long-term cardiac effects of AKI on female mice and indicate that there are important sex-related cardiorenal differences. The role of female sex in cardiovascular outcomes after AKI merits further investigation.
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    Matching Human Unilateral AKI, a Reverse Translational Approach to Investigate Kidney Recovery after Ischemia
    (American Society of Nephrology, 2019-06) Soranno, Danielle E.; Gil, Hyo-Wook; Kirkbride-Romeo, Lara; Altmann, Christopher; Montford, John R.; Yang, Haichun; Levine, Ani; Buchanan, Jane; Faubel, Sarah; Pediatrics, School of Medicine
    Background: The duration of renal ischemia that is associated with (or leads to) renal injury in patients is uncertain, and a reverse translational research approach has been proposed to improve animal models of AKI to facilitate clinical translatability. We developed a two murine models of unilateral renal ischemia to match a recently published human study that investigated renal injury after unilateral renal ischemia during partial nephrectomy. Methods: Eight 10-week-old C57BL/6 male mice underwent left UiAKI or sham procedure, with or without intra-operative ice packs. Functional, histological, and biomarker outcomes were followed at 2, 6 and 24 hours, or 14 or 28 days later. The 14 and 28 day cohorts were duplicated such that contralateral nephrectomy could be performed 3 days prior to sacrifice with functional measurements obtained to isolate the glomerular filtration rate of the injured kidney. Results: The short-term outcomes correlated with the human study findings with urine and serum biomarkers of injury peaking around 24 hours and then normalizing, and reassuring immediate histological outcomes. Functional and histological outcomes at the later time-points (14 and 28 days) demonstrate an increase in fibrosis markers, and a reduction in glomerular filtration rate in the injured kidney, corresponding to the duration of ischemia, while serum and urine biomarkers remained reassuring. Conclusions: Our findings suggest that clinically available biomarkers of renal function are falsely reassuring against long-term injury following UiAKI, and that the duration of ischemia correlates with impaired function and increased fibrosis.
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    Measurement of glomerular filtration rate reveals that subcapsular injection of shear‐thinning hyaluronic acid hydrogels does not impair kidney function in mice
    (Wiley, 2022-03) Soranno, Danielle E.; Kirkbride-Romeo, Lara; Han, Daniel; Altmann, Christopher; Rodell, Christopher B.; Pediatrics, School of Medicine
    The continued development of minimally invasive therapeutic implants, such as injectable hydrogels, necessitates the concurrent advancement of methods to best assess their biocompatibility via functional outcomes in vivo. Biomaterial implants have been studied to treat kidney disease; however, assessment of biocompatibility has been limited to biomarker and histological assessments. Techniques now exist to measure kidney function serially in vivo in murine studies via transcutaneous measurements of glomerular filtration rate (tGFR). In this study, adult male and female wild-type BalbC mice underwent right unilateral nephrectomy. The remaining solitary left kidney was allowed 4 weeks to recover via compensatory hypertrophy, after which subcapsular injection of either saline or shear-thinning hyaluronic acid hydrogel was performed. Serial tGFR measurements before and after treatment were used to assess the effect of hydrogel injection on kidney filtration. Urine and serum biomarkers of kidney function, and kidney histology were also quantified. Hydrogel injection did not affect kidney function, as assessed by tGFR. Results were in agreement with standard metrics of serum and urine biomarkers of injury as well as histological assessment of inflammation. The model developed provides a direct functional assessment of implant compatibility for the treatment of kidney disease and impact on kidney function.
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    Mesenchymal Stem Cells Delivered Locally to Ischemia-Reperfused Kidneys via Injectable Hyaluronic Acid Hydrogels Decrease Extracellular Matrix Remodeling 1 Month after Injury in Male Mice
    (MDPI, 2023-07-04) Han, Daniel S.; Erickson, Christopher; Hansen, Kirk C.; Kirkbride-Romeo, Lara; He, Zhibin; Rodell, Christopher B.; Soranno, Danielle E.; Pediatrics, School of Medicine
    The translation of stem cell therapies has been hindered by low cell survival and retention rates. Injectable hydrogels enable the site-specific delivery of therapeutic cargo, including cells, to overcome these challenges. We hypothesized that delivery of mesenchymal stem cells (MSC) via shear-thinning and injectable hyaluronic acid (HA) hydrogels would mitigate renal damage following ischemia-reperfusion acute kidney injury. Acute kidney injury (AKI) was induced in mice by bilateral or unilateral ischemia-reperfusion kidney injury. Three days later, mice were treated with MSCs either suspended in media injected intravenously via the tail vein, or injected under the capsule of the left kidney, or MSCs suspended in HA injected under the capsule of the left kidney. Serial measurements of serum and urine biomarkers of renal function and injury, as well as transcutaneous glomerular filtration rate (tGFR) were performed. In vivo optical imaging showed that MSCs localized to both kidneys in a sustained manner after bilateral ischemia and remained within the ipsilateral treated kidney after unilateral ischemic AKI. One month after injury, MSC/HA treatment significantly reduced urinary NGAL compared to controls; it did not significantly reduce markers of fibrosis compared to untreated controls. An analysis of kidney proteomes revealed decreased extracellular matrix remodeling and high overlap with sham proteomes in MSC/HA-treated animals. Hydrogel-assisted MSC delivery shows promise as a therapeutic treatment following acute kidney injury.
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    Metabolomics assessment reveals oxidative stress and altered energy production in the heart after ischemic acute kidney injury in mice
    (Elsevier, 2019-03) Fox, Benjamin M.; Gil, Hyo-Wook; Kirkbride-Romeo, Lara; Bagchi, Rushita A.; Wennersten, Sara A.; Haefner, Korey R.; Skrypnyk, Nataliya I.; Brown, Carolyn N.; Soranno, Danielle E.; Gist, Katja M.; Griffin, Benjamin R.; Jovanovich, Anna; Reisz, Julie A.; Wither, Matthew J.; D'Alessandro, Angelo; Edelstein, Charles L.; Clendenen, Nathan; McKinsey, Timothy A.; Altmann, Christopher; Pediatrics, School of Medicine
    Acute kidney injury (AKI) is a systemic disease associated with widespread effects on distant organs, including the heart. Normal cardiac function is dependent on constant ATP generation, and the preferred method of energy production is via oxidative phosphorylation. Following direct ischemic cardiac injury, the cardiac metabolome is characterized by inadequate oxidative phosphorylation, increased oxidative stress, and increased alternate energy utilization. We assessed the impact of ischemic AKI on the metabolomics profile in the heart. Ischemic AKI was induced by 22 minutes of renal pedicle clamping, and 124 metabolites were measured in the heart at 4 hours, 24 hours, and 7 days post-procedure. 41% of measured metabolites were affected, with the most prominent changes observed 24 hours post-AKI. The post-AKI cardiac metabolome was characterized by amino acid depletion, increased oxidative stress, and evidence of alternative energy production, including a shift to anaerobic forms of energy production. These metabolomic effects were associated with significant cardiac ATP depletion and with echocardiographic evidence of diastolic dysfunction. In the kidney, metabolomics analysis revealed shifts suggestive of energy depletion and oxidative stress, which were reflected systemically in the plasma. This is the first study to examine the cardiac metabolome after AKI, and demonstrates that effects of ischemic AKI on the heart are akin to the effects of direct ischemic cardiac injury.