Browsing by Subject "kidney injury"

Now showing 1 - 7 of 7
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    Endothelial STAT3 Modulates Protective Mechanisms in a Mouse Ischemia-Reperfusion Model of Acute Kidney Injury
    (hindawi publishing corporation, 2017) Dube, Shataakshi; Matam, Tejasvi; Yen, Jessica; Mang, Henry E.; Dagher, Pierre C.; Hato, Takashi; Sutton, Timothy A.; Medicine, School of Medicine
    STAT3 is a transcriptional regulator that plays an important role in coordinating inflammation and immunity. In addition, there is a growing appreciation of the role STAT3 signaling plays in response to organ injury following diverse insults. Acute kidney injury (AKI) from ischemia-reperfusion injury is a common clinical entity with devastating consequences, and the recognition that endothelial alterations contribute to kidney dysfunction in this setting is of growing interest. Consequently, we used a mouse with a genetic deletion of Stat3 restricted to the endothelium to examine the role of STAT3 signaling in the pathophysiology of ischemic AKI. In a mouse model of ischemic AKI, the loss of endothelial STAT3 signaling significantly exacerbated kidney dysfunction, morphologic injury, and proximal tubular oxidative stress. The increased severity of ischemic AKI was associated with more robust endothelial-leukocyte adhesion and increased tissue accumulation of F4/80+ macrophages. Moreover, important proximal tubular adaptive mechanisms to injury were diminished in association with decreased tissue mRNA levels of the epithelial cell survival cytokine IL-22. In aggregate, these findings suggest that the endothelial STAT3 signaling plays an important role in limiting kidney dysfunction in ischemic AKI and that selective pharmacologic activation of endothelial STAT3 signaling could serve as a potential therapeutic target.
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    Evolving Concepts in Uromodulin Biology, Physiology, and Its Role in Disease: a Tale of Two Forms
    (American Heart Association, 2022-11) LaFavers, Kaice A.; Micanovic, Radmila; Sabo, Angela R.; Maghak, Lauren A.; El-Achkar, Tarek M.; Medicine, School of Medicine
    Uromodulin (or Tamm-Horsfall protein) is a glycoprotein uniquely produced in the kidney by tubular cells of the thick ascending limb of the loop of Henle and early distal tubules. This protein exhibits bidirectional secretion in the urine and in the renal interstitium and circulation. The role of this protein in maintaining renal and systemic homeostasis is becoming increasingly appreciated. Furthermore, perturbations of its functions may play a role in various diseases affecting the kidney and distant organs. In this review, we will discuss important advances in understanding its biology, highlighting the recent discoveries of its secretion and differential precursor processing that generates two forms: a) a highly polymerizing form that is apically excreted in the urine and generates filaments, and b) a non-polymerizing form that retains a polymerization inhibitory pro-peptide and is released basolaterally in the kidney interstitium and circulation, but can also be found in the urine. We will also discuss factors regulating its production and release, taking into account its intricate physiology, and propose best practices to report its levels. We also discuss breaking advances in its role in hypertension, acute kidney injury and progression to chronic disease, immunomodulation and regulating renal and systemic oxidative stress. We anticipate that this work will be a great resource for researchers and clinicians. This review will highlight the importance of defining what regulates the two forms of uromodulin, so that modulation of uromodulin levels and function could become a novel tool in our therapeutic armamentarium against kidney disease.
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    Histone deacetylase inhibitors protect against cisplatin-induced acute kidney injury by activating autophagy in proximal tubular cells
    (Nature Publishing group, 2018-02-23) Liu, Jing; Livingston, Man J.; Dong, Guie; Tang, Chengyuan; Su, Yunchao; Wu, Guangyu; Yin, Xiao-Ming; Dong, Zheng; Pathology and Laboratory Medicine, School of Medicine
    Histone deacetylase inhibitors (HDACi) have therapeutic effects in models of various renal diseases including acute kidney injury (AKI); however, the underlying mechanism remains unclear. Here we demonstrate that two widely tested HDACi (suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA)) protect the kidneys in cisplatin-induced AKI by enhancing autophagy. In cultured renal proximal tubular cells, SAHA and TSA enhanced autophagy during cisplatin treatment. We further verified the protective effect of TSA against cisplatin-induced apoptosis in these cells. Notably, inhibition of autophagy by chloroquine or by autophagy gene 7 (Atg7) ablation diminished the protective effect of TSA. In mice, TSA increased autophagy in renal proximal tubules and protected against cisplatin-induced AKI. The in vivo effect of TSA was also abolished by chloroquine and by Atg7 knockout specifically from renal proximal tubules. Mechanistically, TSA stimulated AMPK and inactivated mTOR during cisplatin treatment of proximal tubule cells and kidneys in mice. Together, these results suggest that HDACi may protect kidneys by activating autophagy in proximal tubular cells.
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    Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction
    (Informa UK (Taylor & Francis), 2016-06-02) Livingston, Man J.; Ding, Han-Fei; Huang, Shuang; Hill, Joseph A.; Yin, Xiao-Ming; Dong, Zheng; Department of Pathology and Laboratory Medicine, School of Medicine
    Renal fibrosis is the final, common pathway of end-stage renal disease. Whether and how autophagy contributes to renal fibrosis remains unclear. Here we first detected persistent autophagy in kidney proximal tubules in the renal fibrosis model of unilateral ureteral obstruction (UUO) in mice. UUO-associated fibrosis was suppressed by pharmacological inhibitors of autophagy and also by kidney proximal tubule-specific knockout of autophagy-related 7 (PT-Atg7 KO). Consistently, proliferation and activation of fibroblasts, as indicated by the expression of ACTA2/α-smooth muscle actin and VIM (vimentin), was inhibited in PT-Atg7 KO mice, so was the accumulation of extracellular matrix components including FN1 (fibronectin 1) and collagen fibrils. Tubular atrophy, apoptosis, nephron loss, and interstitial macrophage infiltration were all inhibited in these mice. Moreover, these mice showed a specific suppression of the expression of a profibrotic factor FGF2 (fibroblast growth factor 2). In vitro, TGFB1 (transforming growth factor β 1) induced autophagy, apoptosis, and FN1 accumulation in primary proximal tubular cells. Inhibition of autophagy suppressed FN1 accumulation and apoptosis, while enhancement of autophagy increased TGFB1-induced-cell death. These results suggest that persistent activation of autophagy in kidney proximal tubules promotes renal interstitial fibrosis during UUO. The profibrotic function of autophagy is related to the regulation on tubular cell death, interstitial inflammation, and the production of profibrotic factors.
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    Point mutation in D8C domain of Tamm-Horsfall protein/uromodulin in transgenic mice causes progressive renal damage and hyperuricemia
    (PLOS, 2017-11-16) Ma, Lijie; Liu, Yan; Landry, Nichole K.; El-Achkar, Tarek M.; Lieske, John C.; Wu, Xue-Ru; Medicine, School of Medicine
    Hereditary mutations in Tamm-Horsfall protein (THP/uromodulin) gene cause autosomal dominant kidney diseases characterized by juvenile-onset hyperuricemia, gout and progressive kidney failure, although the disease pathogenesis remains unclear. Here we show that targeted expression in transgenic mice of a mutation within the domain of 8 cysteines of THP in kidneys’ thick ascending limb (TAL) caused unfolded protein response in younger (1-month old) mice and apoptosis in older (12-month old) mice. While the young mice had urine concentration defects and polyuria, such defects progressively reversed in the older mice to marked oliguria, highly concentrated urine, fibrotic kidneys and reduced creatinine clearance. Both the young and the old transgenic mice had significantly higher serum uric acid and its catabolic product, allantoin, than age-matched wild-type mice. This THP mutation apparently caused primary defects in TAL by compromising the luminal translocation and reabsorptive functions of NKCC2 and ROMK and secondary responses in proximal tubules by upregulating NHE3 and URAT1. Our results strongly suggest that the progressive worsening of kidney functions reflects the accumulation of the deleterious effects of the misfolded mutant THP and the compensatory responses. Transgenic mice recapitulating human THP/uromodulin-associated kidney diseases could be used to elucidate their pathogenesis and test novel therapeutic strategies.
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    The kidney-brain pathogenic axis in severe falciparum malaria
    (Elsevier, 2023-03-01) Conroy, Andrea L.; Datta, Dibyadyuti; Hoffmann, Angelika; Wassmer, Samuel C.; Pediatrics, School of Medicine
    Severe falciparum malaria is a medical emergency and a leading cause of death and neurodisability in endemic areas. Common complications include acute kidney injury (AKI) and cerebral malaria, and recent studies have suggested links between kidney and brain dysfunction in Plasmodium falciparum infection. Here, we review these new findings and present the hypothesis of a pivotal pathogenic crosstalk between the kidneys and the brain in severe falciparum malaria. We highlight the evidence of a role for distant organ involvement in the development of cerebral malaria and subsequent neurocognitive impairment post-recovery, describe the challenges associated with current diagnostic shortcomings for both AKI and brain involvement in severe falciparum malaria, and explore novel potential therapeutic strategies.
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    Tissue Cytometry With Machine Learning in Kidney: From Small Specimens to Big Data
    (Frontiers, 2022) El-Achkar, Tarek M.; Winfree, Seth; Talukder, Niloy; Barwinska, Daria; Ferkowicz, Michael J.; Al Hasan, Mohammad; Computer and Information Science, School of Science
    Advances in cellular and molecular interrogation of kidney tissue have ushered a new era of understanding the pathogenesis of kidney disease and potentially identifying molecular targets for therapeutic intervention. Classifying cells and identifying subtypes and states induced by injury is a foundational task in this context. High resolution Imaging-based approaches such as large-scale fluorescence 3D imaging offer significant advantages because they allow preservation of tissue architecture and provide a definition of the spatial context of each cell. We recently described the Volumetric Tissue Exploration and Analysis cytometry tool which enables an interactive analysis, quantitation and semiautomated classification of labeled cells in 3D image volumes. We also established and demonstrated an imaging-based classification using deep learning of cells in intact tissue using 3D nuclear staining with 4',6-diamidino-2-phenylindole (DAPI). In this mini-review, we will discuss recent advancements in analyzing 3D imaging of kidney tissue, and how combining machine learning with cytometry is a powerful approach to leverage the depth of content provided by high resolution imaging into a highly informative analytical output. Therefore, imaging a small tissue specimen will yield big scale data that will enable cell classification in a spatial context and provide novel insights on pathological changes induced by kidney disease.