Combinational Use of Antiplatelet Medication Sarpogrelate with Therapeutic Drug Rosuvastatin in Treating High-Cholesterol Diet-Induced Chronic Kidney Disease in ApoE-Deficient Mice

A number of metabolic disorders, including hyperlipidemia, potentially cause chronic kidney disease (CKD), one of their major chronic complications and comorbidities. Rosuvastatin is one of the widely used antiatherogenic drugs among hyperlipidemic patients. Meanwhile, sarpogrelate is not only a 5-hydroxytryptamine receptor antagonist but also an antiplatelet agent, inhibiting platelet-stimulated blood coagulation and improving peripheral circulation. In this study, a combination of sarpogrelate and/or rosuvastatin was used on CKD mice induced by a high-fat diet for 8 weeks. The mice were tested for pathological changes using histological evaluation. Tremendous alterations were found, including a remarked increase in total cholesterol and low-density lipoprotein cholesterol levels, glomerular endothelial proliferation, and mesangial expansion. Also, tubular damage and extracellular matrix accumulation occurred, namely, a marked increase in the macula densa, scattered and apoptotic loss of the apical brush border with vacuolated basophilic cytoplasm and heavily stained nuclei, and expanded Bowman’s space, which were at least partially ameliorated by sarpogrelate and/or rosuvastatin treatment. The analysis of expression profiles at both the RNA and protein levels, using real-time quantitative polymerase chain reaction and Western blot analysis, indicated that LDL-R/CD68/LOX-1-positive monocyte/macrophage-mediated enhanced proinflammatory activation, including the significant upregulation of tumor necrosis factor-α and interleukin-6, was actually attenuated by sarpogrelate and/or rosuvastatin treatment. The findings indicated that sarpogrelate and/or rosuvastatin treatment potentially ameliorates CKD progression in patients with the aforementioned comorbid metabolic disorders.

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Tubular cell-enriched subpopulation of primary renal cells improves survival and augments kidney function in rodent model of chronic kidney disease

AJP Renal Physiology ◽

10.1152/ajprenal.00221.2010 ◽

2010 ◽

Vol 299 (5) ◽

pp. F1026-F1039 ◽

Cited By ~ 45

Author(s):

Rusty Kelley ◽

Eric S. Werdin ◽

Andrew T. Bruce ◽

Sumana Choudhury ◽

Shay M. Wallace ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Kidney Function ◽

Transforming Growth Factor ◽

Kidney Tissue ◽

Tubular Cell ◽

Acute Injury ◽

Treatment Modalities ◽

Histological Evaluation ◽

Renal Cells

Established chronic kidney disease (CKD) may be identified by severely impaired renal filtration that ultimately leads to the need for dialysis or kidney transplant. Dialysis addresses only some of the sequelae of CKD, and a significant gap persists between patients needing transplant and available organs, providing impetus for development of new CKD treatment modalities. Some postulate that CKD develops from a progressive imbalance between tissue damage and the kidney's intrinsic repair and regeneration processes. In this study we evaluated the effect of kidney cells, delivered orthotopically by intraparenchymal injection to rodents 4–7 wk after CKD was established by two-step 5/6 renal mass reduction (NX), on the regeneration of kidney function and architecture as assessed by physiological, tissue, and molecular markers. A proof of concept for the model, cell delivery, and systemic effect was demonstrated with a heterogeneous population of renal cells (UNFX) that contained cells from all major compartments of the kidney. Tubular cells are known contributors to kidney regeneration in situ following acute injury. Initially tested as a control, a tubular cell-enriched subpopulation of UNFX (B2) surprisingly outperformed UNFX. Two independent studies (3 and 6 mo in duration) with B2 confirmed that B2 significantly extended survival and improved renal filtration (serum creatinine and blood urea nitrogen). The specificity of B2 effects was verified by direct comparison to cell-free vehicle controls and an equivalent dose of non-B2 cells. Quantitative histological evaluation of kidneys at 6 mo after treatment confirmed that B2 treatment reduced severity of kidney tissue pathology. Treatment-associated reduction of transforming growth factor (TGF)-β1, plasminogen activator inhibitor (PAI)-1, and fibronectin (FN) provided evidence that B2 cells attenuated canonical pathways of profibrotic extracellular matrix production.

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Tenofovir disoproxil fumarate co-administered with lopinavir/ritonavir is strongly associated with tubular damage and chronic kidney disease

Journal of Infection and Chemotherapy ◽

10.1016/j.jiac.2018.03.002 ◽

2018 ◽

Vol 24 (7) ◽

pp. 549-554 ◽

Cited By ~ 5

Author(s):

Daisuke Mizushima ◽

Dung Thi Hoai Nguyen ◽

Dung Thi Nguyen ◽

Shoko Matsumoto ◽

Junko Tanuma ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Tenofovir Disoproxil Fumarate ◽

Tubular Damage

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Upregulation of Oxidative Stress Related Genes in a Chronic Kidney Disease Attributed to Specific Geographical Locations of Sri Lanka

BioMed Research International ◽

10.1155/2016/7546265 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 7

Author(s):

Saravanabavan Sayanthooran ◽

Dhammika N. Magana-Arachchi ◽

Lishanthe Gunerathne ◽

Tilak D. J. Abeysekera ◽

Suneth S. Sooriyapathirana

Keyword(s):

Oxidative Stress ◽

Chronic Kidney Disease ◽

Sri Lanka ◽

Kidney Disease ◽

Quantitative Polymerase Chain Reaction ◽

Fibroblast Growth Factor 23 ◽

Study Groups ◽

Unknown Etiology ◽

Pyrin Domain ◽

Expression Of Genes

Objective.To infer the influence of internal and external oxidative stress in chronic kidney disease patients of unknown etiology (CKDu) in Sri Lanka, by analyzing expression of genes related directly or indirectly to oxidative stress: glutamate-cysteine ligase catalytic subunit (GCLC), glutathione S-transferase mu 1 (GSTM1), glucose-6-phosphate dehydrogenase (G6PD), fibroblast growth factor-23 (FGF23), and NLR family pyrin domain containing 3 (NLRP3).Methods.Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was carried out for the selected populations: CKDu patients (n=43), chronic kidney disease patients (CKD;n=14), healthy individuals from a CKDu endemic area (GHI;n=9), and nonendemic area (KHI;n=16). Fold changes were quantified relative to KHI.Results.GCLC had greater than threefold upregulation in all three study groups, with a maximum of 7.27-fold upregulation in GHI (p=0.000). GSTM1 was not expressed in 25.6% of CKDu and 42.9% of CKD patients, but CKDu patients expressing GSTM1 showed upregulation of 2.60-fold (p<0.05). Upregulation of FGF23 and NLRP3 genes in CKD and CKDu was observed (p<0.01), with greater fold changes in CKD.Conclusion.Results suggest higher influence of external sources of oxidative stress in CKDu, possibly owing to environmental conditions.

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A functional landscape of chronic kidney disease entities from public transcriptomic data

10.1101/265447 ◽

2018 ◽

Author(s):

Ferenc Tajti ◽

Christoph Kuppe ◽

Asier Antoranz ◽

Mahmoud M. Ibrahim ◽

Hyojin Kim ◽

...

Keyword(s):

Gene Expression ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Gene Expression Data ◽

Molecular Mechanisms ◽

Expression Profiles ◽

Kidney Tissue ◽

Therapeutic Targets ◽

Expression Data ◽

Disease Entities

AbstractTo develop efficient therapies and identify novel early biomarkers for chronic kidney disease an understanding of the molecular mechanisms orchestrating it is essential. We here set out to understand how differences in CKD origin are reflected in gene expression. To this end, we integrated publicly available human glomerular microarray gene expression data for nine kidney disease entities that account for a majority of CKD worldwide. We included data from five distinct studies and compared glomerular gene expression profiles to that of non-tumor parts of kidney cancer nephrectomy tissues. A major challenge was the integration of the data from different sources, platforms and conditions, that we mitigated with a bespoke stringent procedure. This allowed us to perform a global transcriptome-based delineation of different kidney disease entities, obtaining a landscape of their similarities and differences based on the genes that acquire a consistent differential expression between each kidney disease entity and nephrectomy tissue. Furthermore, we derived functional insights by inferring activity of signaling pathways and transcription factors from the collected gene expression data, and identified potential drug candidates based on expression signature matching. We validated representative findings by immunostaining in human kidney biopsies indicating e.g. that the transcription factor FOXM1 is significantly and specifically expressed in parietal epithelial cells in RPGN whereas not expressed in control kidney tissue. These results provide a foundation to comprehend the specific molecular mechanisms underlying different kidney disease entities, that can pave the way to identify biomarkers and potential therapeutic targets. To facilitate this, we provide our results as a free interactive web application: https://saezlab.shinyapps.io/ckd_landscape/.Translational StatementChronic kidney disease is a combination of entities with different etiologies. We integrate and analyse transcriptomics analysis of glomerular from different entities to dissect their different pathophysiology, what might help to identify novel entity-specific therapeutic targets.

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Immunometabolic Dysregulation at the Intersection of Obesity and COVID-19

Frontiers in Immunology ◽

10.3389/fimmu.2021.732913 ◽

2021 ◽

Vol 12 ◽

Author(s):

Collins N. Khwatenge ◽

Marquette Pate ◽

Laura C. Miller ◽

Yongming Sang

Keyword(s):

Diabetes Mellitus ◽

Cardiovascular Disease ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Immune Responses ◽

Metabolic Disorders ◽

Acute Infection ◽

Meta Analyses ◽

Metabolic Comorbidities ◽

Interdisciplinary Intervention

Obesity prevails worldwide to an increasing effect. For example, up to 42% of American adults are considered obese. Obese individuals are prone to a variety of complications of metabolic disorders including diabetes mellitus, hypertension, cardiovascular disease, and chronic kidney disease. Recent meta-analyses of clinical studies in patient cohorts in the ongoing coronavirus-disease 2019 (COVID-19) pandemic indicate that the presence of obesity and relevant disorders is linked to a more severe prognosis of COVID-19. Given the significance of obesity in COVID-19 progression, we provide a review of host metabolic and immune responses in the immunometabolic dysregulation exaggerated by obesity and the viral infection that develops into a severe course of COVID-19. Moreover, sequela studies of individuals 6 months after having COVID-19 show a higher risk of metabolic comorbidities including obesity, diabetes, and kidney disease. These collectively implicate an inter-systemic dimension to understanding the association between obesity and COVID-19 and suggest an interdisciplinary intervention for relief of obesity-COVID-19 complications beyond the phase of acute infection.

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Inhibitors of canonical Wnt signaling pathway and inorganic phosphate imbalance in experimental chronic kidney disease

Nephrology (Saint-Petersburg) ◽

10.36485/1561-6274-2019-236-83-91 ◽

2019 ◽

Vol 23 (6) ◽

pp. 83-91 ◽

Cited By ~ 2

Author(s):

E. O. Bogdanova ◽

O. N. Beresneva ◽

I. M. Zubina ◽

G. T. Ivanova ◽

M. M. Parastaeva ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Bone Turnover ◽

Wnt Signaling ◽

Inorganic Phosphate ◽

Metabolic Disorders ◽

Wnt Signaling Pathway ◽

Serum Concentrations ◽

Canonical Wnt Signaling ◽

Canonical Wnt

BACKGROUND. The molecular mechanisms of the initial stages of inorganic phosphate (Pi) metabolic disorders in chronic kidney disease (CKD) remain poorly understood.THE AIM. To test the hypothesis about changes in canonical Wnt signaling pathway inhibitors biosynthesis and a concomitant decrease in bone turnover as one of early mechanisms of Pi imbalance in CKD.MATERIAL AND METHODS. Creatinine (Cr), inorganic phosphate (Pi), serum parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), osteoprotegerin (OPG), sclerostin (SOST) and Dickkopf-1 (DKK), renal SOST and DKK mRNA expression, albuminuria (Alb), proteinuria (uTP) levels, fractional (FEPi) and daily (uPi24) Pi excretion were analyzed in SHR rats (N = 52) with 3/4 nephrectomy (NE) or sham operation (SO) and observation periods of 2, 4, and 6 months.RESULTS. Experimental model was comparable with 1-2 stages of CKD. In groups NE4 and NE6, the concentration of sPi and renal Pi excretion (FEPi and uPi24) were significantly higher vs corresponding controls SO4 (p = 0.006, p <0.010) and SO6 (p = 0.002, p = 0.028). Serum concentrations of FGF23 and PTH in NE and SO animals did not change significantly. In NE4 and NE6 groups, serum SOST and DKK concentrations were significantly higher vs controls (p <0.049, p <0.043), while the kidney expression SOST and DKK mRNA in NE rats did not change significantly or decreased (p = 0.002, p <0.011). The serum concentration of OPG was higher in the NE6 vs SO6 control (p = 0.028).CONCLUSION. The initial stages of experimental CKD are characterized by an increase in serum concentrations of Dikkopf-1, sclerostin and osteoprotegerin. The obtained data suggest the possible role of canonical Wnt signaling inhibition and reduction of bone turnover in the pathogenesis of Pi metabolic disorders in early stages of CKD.

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Proaterogenic Metabolic Disorders in Patients With Chronic Kidney Disease Nondiabetic Origin: Possibility of Statin Therapy

Kardiologiia ◽

10.18565/cardio.2014.6.40-43 ◽

2014 ◽

Vol 6_2014 ◽

pp. 40-43

Author(s):

T. Solomenchyk Solomenchyk ◽

Kh. Semegen-Bodak Semegen-Bodak ◽

N. Slaba Slaba ◽

G. Tshngryan Tshngryan ◽

O. Klymkovich Klymkovich ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Statin Therapy ◽

Metabolic Disorders

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Assessment of Thrombotic and Bleeding Tendency in Two Mouse Models of Chronic Kidney Disease: Adenine-Diet and 5/6th Nephrectomy

TH Open ◽

10.1055/s-0040-1705138 ◽

2020 ◽

Vol 04 (02) ◽

pp. e66-e76

Author(s):

Camélia Makhloufi ◽

Lydie Crescence ◽

Roxane Darbousset ◽

Nathalie McKay ◽

Ziad A. Massy ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Renal Insufficiency ◽

Mouse Models ◽

Quantitative Polymerase Chain Reaction ◽

Bleeding Tendency ◽

Therapeutic Approaches ◽

New Therapeutic Approaches ◽

Vascular Walls ◽

Severe Renal Insufficiency

AbstractThe coexistence of bleeding and thrombosis in patients with chronic kidney disease (CKD) is frequent and poorly understood. Mouse models are essential to understand complications of CKD and to develop new therapeutic approaches improving the health of patients. We evaluated the hemostasis in two models of renal insufficiency: adenine-diet and 5/6th nephrectomy (5/6Nx). Compared with 5/6Nx mice, mice fed with 0.25% adenine had more severe renal insufficiency and so higher levels of prothrombotic uremic toxins like indoxyl sulfate. More severe renal inflammation and fibrosis were observed in the adenine group, as demonstrated by histological and reverse transcription quantitative polymerase chain reaction experiments. Liver fibrinogen γ chain expression and level of plasma fibrinogen were increased only in adenine mice. In both CKD mouse models, tissue factor (TF) expression was increased in kidney and aorta extracts. Immunochemistry analysis of kidney sections showed that TF is localized in the vascular walls. Thrombin–antithrombin complexes were significantly increased in plasma from both adenine and 5/6Nx mice. Tail bleeding time increased significantly only in adenine mice, whereas platelet count was not significant altered. Finally, results obtained by intravital microscopy after laser-induced endothelial injury showed impaired platelet function in adenine mice and an increase in fibrin generation in 5/6Nx mice. To summarize, adenine diet causes a more severe renal insufficiency compared with 5/6Nx. The TF upregulation and the hypercoagulable state were observed in both CKD models. Bleeding tendency was observed only in the adenine model of CKD that recapitulates the whole spectrum of hemostasis abnormalities observed in advanced human CKD.

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