Browsing by Author "Ullah, Md Mahbub"

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    Mutation of RORγT reveals a role for Th17 cells in both injury and recovery from renal ischemia-reperfusion injury
    (American Physiological Society, 2020-11-01) Mehrotra, Purvi; Ullah, Md Mahbub; Collett, Jason A.; Myers, Sarah L.; Dwinell, Melinda R.; Geurts, Aron M.; Basile, David P.; Anatomy, Cell Biology and Physiology, School of Medicine
    To investigate T helper type 17 (Th17) cells in the setting of acute kidney injury, the gene encoding the master regulator of Th17 cell differentiation, that is, RAR-related orphan receptor-γ (RORγT), was mutated in Lewis rats using CRISPR/Cas9 technology. In response to 40 min of bilateral renal ischemia-reperfusion (I/R), RAR-related orphan receptor C (Rorc)-/- rats were resistant to injury relative to wild-type Rorc+/+ rats. This protection was associated with inhibition of IL-17 expression and reduced infiltration of CD4+ cells, CD8+ cells, B cells, and macrophages. To evaluate the effect of Th17 cells on repair, ischemia was increased to 50 min in Rorc-/- rats. This maneuver equalized the initial level of injury in Rorc-/- and Rorc+/+ rats 1 to 2 days post-I/R based on serum creatinine values. However, Rorc-/- rats, but not Rorc+/+ rats, failed to successfully recover renal function and had high mortality by 4 days post-I/R. Histological assessment of kidney tubules showed evidence of repair by day 4 post-I/R in Rorc+/+ rats but persistent necrosis and elevated cell proliferation in Rorc-/- rats. Adoptive transfer of CD4+ cells from the spleen of Rorc+/+ rats or supplementation of exogenous rIL-17 by an osmotic minipump improved renal function and survival of Rorc-/- rats following 50 min of I/R. This was associated with a relative decrease in the number of M1-type macrophages and a relative increase in the percentage of T regulatory cells. Taken together, these data suggest that Th17 cells have both a deleterious and a beneficial role in kidney injury and recovery, contributing to early postischemic injury and inflammation but also possibly being critical in the resolution of inflammation during kidney repair.
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    Role of renal hypoxia in the progression from acute kidney injury to chronic kidney disease
    (Elsevier, 2019-11) Ullah, Md Mahbub; Basile, David P.; Medicine, School of Medicine
    Over the past 20 years, there has been an increased appreciation of the long-term sequelae of acute kidney injury (AKI) and the potential development of chronic kidney disease (CKD). Several pathophysiologic features have been proposed to mediate AKI to CKD progression including maladaptive alterations in tubular, interstitial, inflammatory, and vascular cells. These alterations likely interact to culminate in the progression to CKD. In this article we focus primarily on evidence of vascular rarefaction secondary to AKI, and the potential mechanisms by which rarefaction occurs in relation to other alterations in tubular and interstitial compartments. We further focus on the potential that rarefaction contributes to renal hypoxia. Consideration of the role of hypoxia in AKI to CKD transition focuses on experimental evidence of persistent renal hypoxia after AKI and experimental maneuvers to evaluate the influence of hypoxia, per se, in progressive disease. Finally, consideration of methods to evaluate hypoxia in patients is provided with the suggestion that noninvasive measurement of renal hypoxia may provide insight into progression in post-AKI patients.
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    Subcutaneous injection of adipose stromal cell-secretome improves renal function and reduces inflammation in established acute kidney injury
    (Springer Nature, 2024-04-24) Ullah, Md Mahbub; Collett, Jason A.; Monroe, Jacob C.; Traktuev, Dmitry; Coleman, Michael; March, Keith L.; Basile, David P.; Anatomy, Cell Biology and Physiology, School of Medicine
    Background: Adipose stromal cells (ASC) are a form of mesenchymal stromal cells that elicit effects primarily via secreted factors, which may have advantages for the treatment of injury or disease. Several previous studies have demonstrated a protective role for MSC/ASC on mitigating acute kidney injury but whether ASC derived factors could hasten recovery from established injury has not been evaluated. Methods: We generated a concentrated secretome (CS) of human ASC under well-defined conditions and evaluated its ability to improve the recovery of renal function in a preclinical model of acute kidney injury (AKI) in rats. 24 h following bilateral ischemia/reperfusion (I/R), rats were randomized following determination of plasma creatinine into groups receiving vehicle -control or ASC-CS treatment by subcutaneous injection (2 mg protein/kg) and monitored for evaluation of renal function, structure and inflammation. Results: Renal function, assessed by plasma creatinine levels, recovered faster in ASC-CS treated rats vs vehicle. The most prominent difference between the ASC-CS treated vs vehicle was observed in rats with the most severe degree of initial injury (Pcr > 3.0 mg/dl 24 h post I/R), whereas rats with less severe injury (Pcr < 2.9 mg/dl) recovered quickly regardless of treatment. The quicker recovery of ASC-treated rats with severe injury was associated with less tissue damage, inflammation, and lower plasma angiopoietin 2. In vitro, ASC-CS attenuated the activation of the Th17 phenotype in lymphocytes isolated from injured kidneys. Conclusions: Taken together, these data suggest that ASC-CS represents a potent therapeutic option to improve established AKI.
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    T helper 17 cells in the pathophysiology of acute and chronic kidney disease
    (The Korean Society of Nephrology, 2021-03) Basile, David P.; Ullah, Md Mahbub; Collet, Jason A.; Mehrotra, Purvi; Anatomy and Cell Biology, School of Medicine
    Both acute and chronic kidney disease have a strong underlying inflammatory component. This review focuses primarily on T helper 17 (Th17) cells as mediators of inflammation and their potential to modulate acute and chronic kidney disease. We provide updated information on factors and signaling pathways that promote Th17 cell differentiation with specific reference to kidney disease. We highlight numerous clinical studies that have investigated Th17 cells in the setting of human kidney disease and provide updated summaries from various experimental animal models of kidney disease indicating an important role for Th17 cells in renal fibrosis and hypertension. We focus on the pleiotropic effects of Th17 cells in different renal cell types as potentially relevant to the pathogenesis of kidney disease. Finally, we highlight studies that present contrasting roles for Th17 cells in kidney disease progression.