Chemokine receptor CCR1: A new target for progressive kidney disease

Infiltrating leukocytes are thought to contribute to the progression of kidney disease. Locally produced chemokines guide circulating leukocytes into the kidney, which renders therapeutic blockade of respective chemokine receptors on the leukocyte surface as potential targets for the inhibition of renal leukocyte recruitment. By using mutant mice and specific antagonists, we found that chemokine receptor CCR1 has non-redundant functions for leukocyte adhesion to activated vascular endothelium and for transendothelial diapedesis. Most importantly, CCR1 blockade with a specific small molecule antagonist can improve injury in several types of progressive kidney disease models, even if treatment is initiated in advanced disease states. Identification of new targets may add to the therapeutic options in chronic kidney disease. Copyright (C) 2005 S. Karger AG, Basel

The role of chemokine receptor CCR1-dependent macrophage recruitment for the progression of chronic kidney disease in murine Alport syndrome or type 2 diabetes

The global burden of chronic kidney diseases remains an ongoing medical challenge. Therapies that can halt or reverse advanced renal injury are not yet available. Increasing numbers of patients progress to the end-stage renal failure and require renal replacement therapy, the latter being associated with significant mortality, a lower quality of life, and high costs for national health systems. Thus, new treatment strategies that slow down, halt or even revert progressive renal damage are requested. Chemokines and their receptors are involved in the pathogenesis of renal diseases. They mediate leukocytes and macrophages recruitment and activation during initiation as well as progression of renal inflammation. Infiltrating leukocytes are the major source for proinflammatory and profibrotic cytokines and are therefore critical for mediating fibroblast proliferation, differentiation into myofibroblasts, matrix production, and tubular atrophy. Recent advances in the understanding of the molecular mechanisms that regulate renal leukocyte recruitment suggest chemokines and chemokine receptors as novel targets for specific pharmacological intervention. The aim of the present thesis was to investigate the role of chemokine receptor CCR1 for the progression of chronic kidney diseases, e.g. Alport disease and diabetic nephropathy. Two different animal models were used: Col4A3-deficient mice and type 2 diabetic db/db mice with advanced diabetic nephropathy. We blocked CCR1 in Col4A3-deficient mice with BX417, a small molecule CCR1 antagonist, and BL5923, a novel orally available antagonist with a high specificity for human and murine CCR1 in uninephrectomized type 2 diabetic db/db mice, respectively. Treatment with BX471 (25mg/kg) from weeks 6 to 10 of life improved survival of COL4A3- deficient mice, characterized by glomerulosclerosis and subsequent progressive tubulointerstitial injury, leading to fatal end-stage renal disease (ESRD). Improvement was associated with less interstitial macrophages, apoptotic tubular epithelial cells, tubular atrophy, interstitial fibrosis, and less globally sclerotic glomeruli. BX471 reduced total renal Ccl5 mRNA expression by reducing the number of interstitial CCL5-positive cells in inflammatory cell infiltrates. Intravital microscopy of the cremaster muscle in male mice identified that BX471 or lack of CCR1 impaired leukocyte adhesion to activated vascular endothelium and transendothelial leukocyte migration, whereas leukocyte rolling and interstitial migration were not affected. Furthermore, in activated murine macrophages, BX471 completely blocked CCL3-induced CCL5 production. When CCR1 was blocked with BL5923 (60mg/kg, b.i.d), the interstitial recruitment of ex vivo labeled macrophages was markedly decreased in uninephrectomized male db/db mice with type 2 diabetes. Similarly, BL5923 orally administered from month 5 to 6 of life reduced the numbers of interstitial macrophages in uninephrectomized db/db mice. This was associated with reduced numbers of Ki-67 proliferating tubular epithelial and interstitial cells, tubular atrophy, and interstitial fibrosis in uninephrectomized db/db mice. Glomerular pathology and proteinuria were not affected by the CCR1 antagonist. BL5923 reduced renal mRNA expression of Ccl2, Ccr1, Ccr2, Ccr5, Tgf-β1, and collagen I-α1 when compared to untreated uninephrectomized male db/db mice of the same age. Thus, we identified a previously unrecognized role for CCR1-dependent recruitment of interstitial macrophages for the progression of chronic kidney disease in Alport disease and diabetic nephropathy. These data identify CCR1 as a potential therapeutic target for Alport disease and late stage diabetic nephropathy or other progressive nephropathies associated with interstitial macrophage infiltrates

Private pension provision in ukraine: state and prospects

Обґрунтовано необхідність впровадження трьохрівневої пенсійної системи. Здійснено аналіз роботи інститутів системи добровільного недержавного пенсійного забезпечення. Визначено розбіжності між суб’єктами недержавного пенсійного забезпечення. The article deals with the necessity of introducing a three level pension system. It analyses the activities of the institutes of private pension provision. The differences between the subjects of private pension provision are determined

Toll-Like Receptor Signaling and SIGIRR in Renal Fibrosis upon Unilateral Ureteral Obstruction

Innate immune activation via IL-1R or Toll-like receptors (TLR) contibutes to acute kidney injury but its role in tissue remodeling during chronic kidney disease is unclear. SIGIRR is an inhibitor of TLR-induced cytokine and chemokine expression in intrarenal immune cells, therefore, we hypothesized that Sigirr-deficiency would aggravate postobstructive renal fibrosis. The expression of TLRs as well as endogenous TLR agonists increased within six days after UUO in obstructed compared to unobstructed kidneys while SIGIRR itself was downregulated by day 10. However, lack of SIGIRR did not affect the intrarenal mRNA expression of proinflammatory and profibrotic mediators as well as the numbers of intrarenal macrophages and T cells or morphometric markers of tubular atrophy and interstitial fibrosis. Because SIGIRR is known to block TLR/IL-1R signaling at the level of the intracellular adaptor molecule MyD88 UUO experiments were also performed in mice deficient for either MyD88, TLR2 or TLR9. After UUO there was no significant change of tubular interstitial damage and interstitial fibrosis in neither of these mice compared to wildtype counterparts. Additional in-vitro studies with CD90+ renal fibroblasts revealed that TLR agonists induce the expression of IL-6 and MCP-1/CCL2 but not of TGF-β, collagen-1α or smooth muscle actin. Together, postobstructive renal interstitial fibrosis and tubular atrophy develop independent of SIGIRR, TLR2, TLR9, and MyD88. These data argue against a significant role of these molecules in renal fibrosis

Tissue Microenvironments Define and Get Reinforced by Macrophage Phenotypes in Homeostasis or during Inflammation, Repair and Fibrosis

Current macrophage phenotype classifications are based on distinct in vitro culture conditions that do not adequately mirror complex tissue environments. In vivo monocyte progenitors populate all tissues for immune surveillance which supports the maintenance of homeostasis as well as regaining homeostasis after injury. Here we propose to classify macrophage phenotypes according to prototypical tissue environments, e.g. as they occur during homeostasis as well as during the different phases of (dermal) wound healing. In tissue necrosis and/or infection, damage- and/or pathogen-associated molecular patterns induce proinflammatory macrophages by Toll-like receptors or inflammasomes. Such classically activated macrophages contribute to further tissue inflammation and damage. Apoptotic cells and antiinflammatory cytokines dominate in postinflammatory tissues which induce macrophages to produce more antiinflammatory mediators. Similarly, tumor-associated macrophages also confer immunosuppression in tumor stroma. Insufficient parenchymal healing despite abundant growth factors pushes macrophages to gain a profibrotic phenotype and promote fibrocyte recruitment which both enforce tissue scarring. Ischemic scars are largely devoid of cytokines and growth factors so that fibrolytic macrophages that predominantly secrete proteases digest the excess extracellular matrix. Together, macrophages stabilize their surrounding tissue microenvironments by adapting different phenotypes as feed-forward mechanisms to maintain tissue homeostasis or regain it following injury. Furthermore, macrophage heterogeneity in healthy or injured tissues mirrors spatial and temporal differences in microenvironments during the various stages of tissue injury and repair. Copyright (C) 2012 S. Karger AG, Base

Characteristics and analysis of risk management for commercial business activities

Список використаних джерел 1. Мануйленко, В. В., & Рызин, Д. А. (2017). Комплексная субъектно-объектная характеристика понятия «финансовый риск» в коммерческой корпоративной организации. Евразийский юридический журнал, (6), 288-291. 2. Семенова, К. Д., Тарасова, К. І., Семенова, Е. Д., & Тарасова, К. И. (2013). Виявлення та оцінка ризиків як елемент забезпечення конкурентоспроможності підприємства. Атлант. С. 337–352. 3. Радаев, Н. Н., & Боридько, С. И. (2005). Оценка риска при принятии решений в рисковых ситуациях. Измерительная техника, (9), 27-29. 4. Петровська, С. В., & Костюк, І. В. (2015). Проблеми розвитку інвестиційної діяльності комерційних банків. Проблеми системного підходу в економіці, (53), 59-63. 5. Кузьмина, Н. В. (2017). Риски в предпринимательской деятельности: историкоэкономический аспект. Экономика строительства и природопользования, (4 (65)). 6. Олешко, Т. І., Гребенюк, С. В. (2018). Теоретико-ігрове моделювання задачі страхування авіаційних ризиків. економічні студії, 117-119. 7. Керування ризиком. Методи загального оцінювання ризику (ІЕС/ISO 31010:2009, IDT). ДСТУ ІЕС/ISO 31010:2013. – К.: Мінекономрозвитку України. 2015. – 73 с 8. Гужин, А. А., & Ежкова, В. Г. (2017). Риск-менеджмент и методы управления рисками. Инновации и инвестиции, (2), 185-189. 9. Ткаченко, С. Є. (2017). Теоретичні засади управління фінансовими ризиками підприємства. Вісник Харківського національного технічного університету сільського господарства імені Петра Василенка, (188), 169-177. 10. Донець Л.І. (2012) Загальна схема процесу управління ризиком. Обгрунтування господарських рішень та оцінювання ризиків. С. 264. 11. Юдін, О. К., Фролов, О. В., & Бойко, Ю. П. (2015). Організація систем підтримки прийняття рішень для управління в кризових ситуаціях. Наукоємні технології, (3), 244-249. 12. Илышева Н.Н., Каранина Е.В. Стратегический анализ риск-системы предприятия как новое направление экономического анализа // Экономический анализ: теория и практика. 2013. №14 (317).У статті проведено опис ризикових ситуацій, причини виникнення ризику, підходи до управління ризиками на комерційному підприємстві, показано зв’язок між стратегією підприємства з управління ризиками та його діяльністю. Показано, що для ефективної роботи з ризиком підприємству необхідно мати свою систему управління ризиком, яка використовується з метою вибору прийнятного рівня ризику та пошуку способів зниження його негативних наслідків, адже розвиток ринкових відносин підсилює значущість роботи з управління ризиками в підприємствах роздрібної торгівлі, що пов'язано зі збільшенням обсягів інформації, прискоренням "ритму життя" та іншими рисами, що характеризують економіку ринкового типу. Запропоновано загальну схему технології управління ризиком комерційного підприємств з метою здійснення аналізу та оцінки ризику, вироблення способів його зниження при управлінні комерційним підприємством.The article describes the risk situations, causes of risk, approaches to risk management in a commercial enterprise, shows the relationship between the strategy of the risk management company and its activities. It is shown that in order to work effectively with risk, an enterprise must have its own risk management system, which is used to select an acceptable level of risk and to find ways to reduce its negative consequences, because the development of market relations enhances the importance of risk management work in retailers due to the increase in the amount of information, the acceleration of the "rhythm of life" and other traits that characterize a market economy. The general scheme of technology of risk management of commercial enterprises is offered with the purpose of carrying out the analysis and estimation of risk, working out of ways to reduce it when managing a commercial enterprise