Browsing by Author "Okamura, Kayo"

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    Circulating IL-6 upregulates IL-10 production in splenic CD4 + T cells and limits acute kidney injury-induced lung inflammation
    (Elsevier, 2017-05) Andres-Hernando, Ana; Okamura, Kayo; Bhargava, Rhea; Kiekhaefer, Carol M.; Soranno, Danielle E.; Kirkbride-Romeo, Lara A.; Gil, Hyo-wook; Altmann, Chris; Faubel, Sarah; Pediatrics, School of Medicine
    Although it is well established that acute kidney injury (AKI) is a proinflammatory state, little is known about the endogenous counter-inflammatory response. IL-6 is traditionally considered a pro-inflammatory cytokine that is elevated in the serum in both human and murine AKI. However, IL-6 is known to have anti-inflammatory effects. Here we sought to investigate the role of IL-6 in the counter-inflammatory response after AKI, particularly in regard to the anti-inflammatory cytokine IL-10. Ischemic AKI was induced by bilateral renal pedicle clamping. IL-10-deficient mice had increased systemic and lung inflammation after AKI, demonstrating the role of IL-10 in limiting inflammation after AKI. We then sought to determine whether IL-6 mediates IL-10 production. Wild-type mice with AKI had a marked upregulation of splenic IL-10 that was absent in IL-6-deficient mice with AKI. In vitro, addition of IL-6 to splenocytes increased IL-10 production in CD4+ T cells, B cells, and macrophages. In vivo, CD4-deficient mice with AKI had reduced splenic IL-10 and increased lung myeloperoxidase activity. Thus, IL-6 directly increases IL-10 production and participates in the counter-inflammatory response after AKI.
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    Early peritoneal dialysis reduces lung inflammation in mice with ischemic acute kidney injury
    (Elsevier, 2017-08) Altmann, Chris; Ahuja, Nilesh; Kiekhaefer, Carol M.; Andres Hernando, Ana; Okamura, Kayo; Bhargava, Rhea; Duplantis, Jane; Kirkbride-Romero, Lara A.; Huckles, Jill; Fox, Benjamin M.; Kahn, Kashfi; Soranno, Danielle E.; Gil, Hyo-wook; Teitelbaum, Isaac; Faubel, Sarah; Pediatrics, School of Medicine
    Although dialysis has been used in the care of patients with acute kidney injury (AKI) for over 50 years, very little is known about the potential benefits of uremic control on systemic complications of AKI. Since the mortality of AKI requiring renal replacement therapy (RRT) is greater than half in the intensive care unit, a better understanding of the potential of RRT to improve outcomes is urgently needed. Therefore, we sought to develop a technically feasible and reproducible model of RRT in a mouse model of AKI. Models of low- and high-dose peritoneal dialysis (PD) were developed and their effect on AKI, systemic inflammation, and lung injury after ischemic AKI was examined. High-dose PD had no effect on AKI, but effectively cleared serum IL-6, and dramatically reduced lung inflammation, while low-dose PD had no effect on any of these three outcomes. Both models of RRT using PD in AKI in mice reliably lowered urea in a dose-dependent fashion. Thus, use of these models of PD in mice with AKI has great potential to unravel the mechanisms by which RRT may improve the systemic complications that have led to increased mortality in AKI. In light of recent data demonstrating reduced serum IL-6 and improved outcomes with prophylactic PD in children, we believe that our results are highly clinically relevant.
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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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    IL-6-mediated hepatocyte production is the primary source of plasma and urine neutrophil gelatinase associated lipocalin during acute kidney injury
    (Elsevier, 2020-05) Skrypnyk, Nataliya I.; Gist, Katja M.; Okamura, Kayo; Montford, John R.; You, Zhiying; Yang, Haichun; Moldovan, Radu; Bodoni, Evelyn; Blaine, Judith T.; Edelstein, Charles L.; Soranno, Danielle E.; Kirkbride-Romeo, Lara A.; Griffin, Benjamin R.; Altmann, Chris; Faubel, Sarah; Pediatrics, School of Medicine
    Neutrophil gelatinase associated lipocalin (NGAL, Lcn2) is the most widely studied biomarker of acute kidney injury (AKI). Previous studies have demonstrated that NGAL is produced by the kidney and released into the urine and plasma. Consequently, NGAL is currently considered a tubule specific injury marker of AKI. However, the utility of NGAL to predict AKI has been variable suggesting that other mechanisms of production are present. IL-6 is a proinflammatory cytokine increased in plasma by two hours of AKI and mediates distant organ effects. Herein, we investigated the role of IL-6 in renal and extra-renal NGAL production. Wild type mice with ischemic AKI had increased plasma IL-6, increased hepatic NGAL mRNA, increased plasma NGAL, and increased urine NGAL; all reduced in IL-6 knockout mice. Intravenous IL-6 in normal mice increased hepatic NGAL mRNA, plasma NGAL and urine NGAL. In mice with hepatocyte specific NGAL deletion (Lcn2hep-/-) and ischemic AKI, hepatic NGAL mRNA was absent, and plasma and urine NGAL were reduced. Since urine NGAL levels appear to be dependent on plasma levels, the renal handling of circulating NGAL was examined using recombinant human NGAL. After intravenous recombinant human NGAL administration to mice, human NGAL in mouse urine was detected by ELISA during proximal tubular dysfunction, but not in pre-renal azotemia. Thus, during AKI, IL-6 mediates hepatic NGAL production, hepatocytes are the primary source of plasma and urine NGAL, and plasma NGAL appears in the urine during proximal tubule dysfunction. Hence, our data change the paradigm by which NGAL should be interpreted as a biomarker of AKI.
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    Prolonged acute kidney injury exacerbates lung inflammation at 7 days post‐acute kidney injury
    (Wiley, 2014-07-22) Andres-Hernando, Ana; Altmann, Christopher; Bhargava, Rhea; Okamura, Kayo; Bacalja, Jasna; Hunter, Brandi; Ahuja, Nilesh; Soranno, Danielle; Faubel, Sarah; Pediatrics, School of Medicine
    Patients with acute kidney injury (AKI) have increased mortality; data suggest that the duration, not just severity, of AKI predicts increased mortality. Animal models suggest that AKI is a multisystem disease that deleteriously affects the lungs, heart, brain, intestine, and liver; notably, these effects have only been examined within 48 h, and longer term effects are unknown. In this study, we examined the longer term systemic effects of AKI, with a focus on lung injury. Mice were studied 7 days after an episode of ischemic AKI (22 min of renal pedicle clamping and then reperfusion) and numerous derangements were present including (1) lung inflammation; (2) increased serum proinflammatory cytokines; (3) liver injury; and (4) increased muscle catabolism. Since fluid overload may cause respiratory complications post-AKI and fluid management is a critical component of post-AKI care, we investigated various fluid administration strategies in the development of lung inflammation post-AKI. Four different fluid strategies were tested - 100, 500, 1000, or 2000 μL of saline administered subcutaneously daily for 7 days. Interestingly, at 7 days post-AKI, the 1000 and 2000 μL fluid groups had less severe AKI and less severe lung inflammation versus the 100 and 500 μL groups. In summary, our data demonstrate that appropriate fluid management after an episode of ischemic AKI led to both (1) faster recovery of kidney function and (2) significantly reduced lung inflammation, consistent with the notion that interventions to shorten AKI duration have the potential to reduce complications and improve patient outcomes.