Browsing by Author "Kelly, K. J."

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    Impaired microvascular circulation in distant organs following renal ischemia
    (Public Library of Science, 2023-06-02) Dominguez, Jesus H.; Xie, Danhui; Kelly, K. J.; Medicine, School of Medicine
    Mortality in acute kidney injury (AKI) patients remains very high, although very important advances in understanding the pathophysiology and in diagnosis and supportive care have been made. Most commonly, adverse outcomes are related to extra-renal organ dysfunction and failure. We and others have documented inflammation in remote organs as well as microvascular dysfunction in the kidney after renal ischemia. We hypothesized that abnormal microvascular flow in AKI extends to distant organs. To test this hypothesis, we employed intravital multiphoton fluorescence imaging in a well-characterized rat model of renal ischemia/reperfusion. Marked abnormalities in microvascular flow were seen in every organ evaluated, with decreases up to 46% observed 48 hours postischemia (as compared to sham surgery, p = 0.002). Decreased microvascular plasma flow was found in areas of erythrocyte aggregation and leukocyte adherence to endothelia. Intravital microscopy allowed the characterization of the erythrocyte formations as rouleaux that flowed as one-dimensional aggregates. Observed microvascular abnormalities were associated with significantly elevated fibrinogen levels. Plasma flow within capillaries as well as microthrombi, but not adherent leukocytes, were significantly improved by treatment with the platelet aggregation inhibitor dipyridamole. These microvascular defects may, in part, explain known distant organ dysfunction associated with renal ischemia. The results of these studies are relevant to human acute kidney injury.
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    Renal, but not platelet or skin, extracellular vesicles decrease oxidative stress, enhance nascent peptide synthesis, and protect from ischemic renal injury
    (American Physiological Society, 2023) Dominguez, Jesus H.; Xie, Danhui; Kelly, K. J.; Medicine, School of Medicine
    Acute kidney injury (AKI) is deadly and expensive, and specific, effective therapy remains a large unmet need. We have demonstrated the beneficial effects of transplanted adult tubular cells and extracellular vesicles (EVs; exosomes) derived from those renal cells on experimental ischemic AKI, even when administered after renal failure is established. To further examine the mechanisms of benefit with renal EVs, we tested the hypothesis that EVs from other epithelia or platelets (a rich source of EVs) might be protective, using a well-characterized ischemia-reperfusion model. When given after renal failure was present, renal EVs, but not those from skin or platelets, markedly improved renal function and histology. The differential effects allowed us to examine the mechanisms of benefit with renal EVs. We found significant decreases in oxidative stress postischemia in the renal EV-treated group with preservation of renal superoxide dismutase and catalase as well as increases in anti-inflammatory interleukin-10. In addition, we propose a novel mechanism of benefit: renal EVs enhanced nascent peptide synthesis following hypoxia in cells and in postischemic kidneys. Although EVs have been used therapeutically, these results serve as "proof of principle" to examine the mechanisms of injury and protection. NEW & NOTEWORTHY: Acute kidney injury is common and deadly, yet the only approved treatment is dialysis. Thus, a better understanding of injury mechanisms and potential therapies is needed. We found that organ-specific, but not extrarenal, extracellular vesicles improved renal function and structure postischemia when given after renal failure occurred. Oxidative stress was decreased and anti-inflammatory interleukin-10 increased with renal, but not skin or platelet, exosomes. We also propose enhanced nascent peptide synthesis as a novel protective mechanism.
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    Role of coagulation in persistent renal ischemia following reperfusion in an animal model
    (American Physiological Society, 2022) Dominguez, Jesus H.; Xie, Danhui; Dominguez, James M., II; Kelly, K. J.; Medicine, School of Medicine
    Ischemic acute kidney injury is common, deadly, and accelerates the progression of chronic kidney disease, yet has no specific therapy. After ischemia, reperfusion is patchy with early and persistent impairment in regional renal blood flow and cellular injury. We tested the hypothesis that intrarenal coagulation results in sustained renal ischemia following reperfusion, using a well-characterized model. Markedly decreased, but heterogeneous, microvascular plasma flow with microthrombi was found postischemia by intravital microscopy. Widespread tissue factor expression and fibrin deposition were also apparent. Clotting was accompanied by complement activation and inflammation. Treatment with exosomes derived from renal tubular cells or with the fibrinolytic urokinase, given 24 h postischemia when renal failure was established, significantly improved microvascular flow, coagulation, serum creatinine, and histological evidence of injury. These data support the hypothesis that intrarenal clotting occurs early and the resultant sustained ischemia is a critical determinant of renal failure following ischemia; they demonstrate that the coagulation abnormalities are amenable to therapy and that therapy results in improvement in both function and postischemic inflammation. NEW & NOTEWORTHY: Ischemic renal injury carries very high morbidity and mortality, yet has no specific therapy. We found markedly decreased, heterogeneous microvascular plasma flow, tissue factor induction, fibrin deposition, and microthrombi after renal ischemia-reperfusion using a well-characterized model. Renal exosomes or the fibrinolytic urokinase, administered after renal failure was established, improved microvascular flow, coagulation, renal function, and histology. Data demonstrate that intrarenal clotting results in sustained ischemia amenable to therapy that improves both function and postischemic inflammation.
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    Role of coagulation in persistent renal ischemia following reperfusion in an animal model
    (American Physiological Society, 2022-11) Dominguez, Jesus H.; Xie, Danhui; Dominguez, James M., 2nd; Kelly, K. J.; Medicine, School of Medicine
    Ischemic acute kidney injury is common, deadly, and accelerates the progression of chronic kidney disease, yet has no specific therapy. After ischemia, reperfusion is patchy with early and persistent impairment in regional renal blood flow and cellular injury. We tested the hypothesis that intrarenal coagulation results in sustained renal ischemia following reperfusion, using a well-characterized model. Markedly decreased, but heterogeneous, microvascular plasma flow with microthrombi was found postischemia by intravital microscopy. Widespread tissue factor expression and fibrin deposition were also apparent. Clotting was accompanied by complement activation and inflammation. Treatment with exosomes derived from renal tubular cells or with the fibrinolytic urokinase, given 24 h postischemia when renal failure was established, significantly improved microvascular flow, coagulation, serum creatinine, and histological evidence of injury. These data support the hypothesis that intrarenal clotting occurs early and the resultant sustained ischemia is a critical determinant of renal failure following ischemia; they demonstrate that the coagulation abnormalities are amenable to therapy and that therapy results in improvement in both function and postischemic inflammation. NEW & NOTEWORTHY Ischemic renal injury carries very high morbidity and mortality, yet has no specific therapy. We found markedly decreased, heterogeneous microvascular plasma flow, tissue factor induction, fibrin deposition, and microthrombi after renal ischemia-reperfusion using a well-characterized model. Renal exosomes or the fibrinolytic urokinase, administered after renal failure was established, improved microvascular flow, coagulation, renal function, and histology. Data demonstrate that intrarenal clotting results in sustained ischemia amenable to therapy that improves both function and postischemic inflammation.