scholarly journals The effect of compound DM509 on kidney fibrosis in the conditions of the experimental model

2020 ◽  
Vol 80 (1) ◽  
pp. 10-15
Author(s):  
A. Stavniichuk ◽  
O. Savchuk ◽  
Abdul Hye Khan ◽  
Wojciech K. Jankiewicz ◽  
John D. Imig ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Renal Failure ◽  
Kidney Disease ◽  
Renal Dysfunction ◽  
Ureteral Obstruction ◽  
Renal Fibrosis ◽  
Unilateral Ureteral Obstruction ◽  
Control Group ◽  
Urea Nitrogen ◽  
Kidney Fibrosis

Kidney fibrosis is a key event in the development of chronic kidney disease, leading to end-stage renal failure. Unfortunately, there are now few drugs capable of preventing fibrosis in the kidneys, which is accompanied by the progression of chronic kidney disease in the terminal stage of renal failure. The results show the effectiveness of the use of a new dual-acting agent DM509 in the prevention of renal fibrosis using a model of unilateral obstruction of the ureter in mice. DM509 is both a farnesoid X-receptor agonist and a soluble epoxyhydrolase inhibitor. In this study, there were 8-12 week old C57BL/6J males undergoing surgery, which led to the development of unilateral ureteral obstruction and a control group. Mice received DM509 (10 mg/kg/day) or DM509-free solution together with drinking water for 10 days the day before surgery. Samples of kidney and blood tissues were collected at the end of the experiment. In the unilateral ureteral obstruction group, kidney dysfunction was detected, which was accompanied by increased urea nitrogen content in the blood compared to the control group (63 ± 7 vs. 34 ± 6 mg/d). The reduction of urea nitrogen in the blood by 36 % in mice with unilateral ureteral obstruction treated with DM509 is shown compared to mice with this pathology without treatment, which in turn proved the effectiveness of DM509 in preventing renal dysfunction. In mice with unilateral ureteral obstruction, which did not receive DM509, the development of kidney fibrosis with a high content of hydroxyproline in the kidneys and also increased collagen content in histological sections of the kidneys were detected. In the DM509 group, the renal and collagen hydroxyproline content was 34-66 % lower, indicating the effectiveness of this agent in the treatment of renal fibrosis. Thus, we have shown that the new DM509 is effective in preventing renal dysfunction and renal fibrosis using a murine model of unilateral ureteral obstruction.

scholarly journals NLRP3 Deficiency Attenuates Renal Fibrosis and Ameliorates Mitochondrial Dysfunction in a Mouse Unilateral Ureteral Obstruction Model of Chronic Kidney Disease

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Honglei Guo ◽  
Xiao Bi ◽  
Ping Zhou ◽  
Shijian Zhu ◽  
Wei Ding
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Mitochondrial Dysfunction ◽  
Ureteral Obstruction ◽  
Renal Fibrosis ◽  
Unilateral Ureteral Obstruction ◽  
Tubulointerstitial Fibrosis ◽  
Mitochondrial Morphology ◽  
Glomerular Injury ◽  
Matrix Deposition

Background and Aims. The nucleotide-binding domain and leucine-rich repeat containing PYD-3 (NLRP3) inflammasome has been implicated in the pathogenesis of chronic kidney disease (CKD); however, its exact role in glomerular injury and tubulointerstitial fibrosis is still undefined. The present study was performed to identify the function of NLRP3 in modulating renal injury and fibrosis and the potential involvement of mitochondrial dysfunction in the murine unilateral ureteral obstruction (UUO) model of CKD. Methods. Employing wild-type (WT) and NLRP3−/− mice with or without UUO, we evaluated renal structure, tissue injury, and mitochondrial ultrastructure, as well as expression of some vital molecules involved in the progression of fibrosis, apoptosis, inflammation, and mitochondrial dysfunction. Results. The severe glomerular injury and tubulointerstitial fibrosis induced in WT mice by UUO was markedly attenuated in NLRP3−/− mice as evidenced by blockade of extracellular matrix deposition, decreased cell apoptosis, and phenotypic alterations. Moreover, NLRP3 deletion reversed UUO-induced impairment of mitochondrial morphology and function. Conclusions. NLRP3 deletion ameliorates mitochondrial dysfunction and alleviates renal fibrosis in a murine UUO model of CKD.

scholarly journals P0852PERICYTE-SPECIFIC MANIPULATION OF HYPOXIA-INDUCIBLE FACTORS REGULATES ERYTHROPOIESIS WITHOUT AGGRAVATING RENAL FIBROSIS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Pei-Zhen Cai ◽  
SZU-YU PAN ◽  
SHUEI-LIONG LIN
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Animal Models ◽  
Ureteral Obstruction ◽  
Renal Fibrosis ◽  
Mrna Level ◽  
Hypoxia Inducible Factor ◽  
Unilateral Ureteral Obstruction ◽  
Hypoxia Inducible Factors ◽  
Picrosirius Red

Abstract Background and Aims Stabilizers of hypoxia-inducible factor (HIF) have been shown to be effective on treatment of anemia in patients with chronic kidney disease (CKD). Increased erythropoietin (EPO) production and enhanced erythropoiesis are known to be the major mechanisms responsible for the treatment effects. However, the effect of HIF stabilization on renal fibrosis is controversial. We created animal models characterized by CKD and pericyte-specific stabilization of HIF to examine the effects of HIF on renal fibrosis and erythropoiesis. Method Gli1CreERT2/+;Egln1F/F, Gli1CreERT2/+;VhlF/F, and Gli1CreERT2/+;Hif1aF/F;Hif2aF/F mice were generated to study the effects of pericyte-specific overexpression or knockout of Hif. Unilateral ureteral obstruction (UUO) was used to induce CKD. The severity of fibrosis was determined by Picrosirius red stain and Col1a1 mRNA level in the kidney. Results Pericyte-specific stabilization of HIF resulted in increased serum EPO level, augmented splenic erythropoiesis, and polycythemia, while the severity of renal fibrosis was not affected. In line with these findings, pericyte-specific knockout of Hif1a or Hif2a did not result in significant change of renal fibrosis. Conclusion Our study endorses the neutral effects of pericyte-specific HIF stabilization on renal fibrosis.

scholarly journals Chronic kidney disease induced in mice by reversible unilateral ureteral obstruction is dependent on genetic background

2010 ◽  
Vol 298 (4) ◽  
pp. F1024-F1032 ◽  
Author(s):  
Tipu S. Puri ◽  
Mohammed I. Shakaib ◽  
Anthony Chang ◽  
Liby Mathew ◽  
Oladunni Olayinka ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Injury ◽  
Ureteral Obstruction ◽  
Genetic Background ◽  
Renal Fibrosis ◽  
Genetic Basis ◽  
Cellular Responses ◽  
Unilateral Ureteral Obstruction ◽  
Number Of Factors

Chronic kidney disease (CKD) begins with renal injury; the progression thereafter depends upon a number of factors, including genetic background. Unilateral ureteral obstruction (UUO) is a well-described model of renal fibrosis and as such is considered a model of CKD. We used an improved reversible unilateral ureteral obstruction (rUUO) model in mice to study the strain dependence of development of CKD after obstruction-mediated injury. C57BL/6 mice developed CKD after reversal of three or more days of ureteral obstruction as assessed by blood urea nitrogen (BUN) measurements (>40 mg/dl). In contrast, BALB/c mice were resistant to CKD with up to 10 days ureteral obstruction. During rUUO, C57BL/6 mice exhibited pronounced inflammatory and intrinsic proliferative cellular responses, disruption of renal architecture, and ultimately fibrosis. By comparison, BALB/c mice had more controlled and measured extrinsic and intrinsic responses to injury with a return to normal within several weeks after release of ureteral obstruction. Our findings provide a model that allows investigation of the genetic basis of events during recovery from injury that contribute to the development of CKD.

scholarly journals Inhibition of PTEN Activity Aggravates Post Renal Fibrosis in Mice with Ischemia Reperfusion-Induced Acute Kidney Injury

2017 ◽  
Vol 43 (5) ◽  
pp. 1841-1854 ◽  
Author(s):  
Jun Zhou ◽  
Jiying  Zhong ◽  
Sen  Lin ◽  
Zhenxing Huang ◽  
Hongtao Chen ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Smooth Muscle Actin ◽  
Ischemia Reperfusion ◽  
Specific Inhibitor ◽  
Kidney Injury ◽  
Control Group ◽  
Kidney Fibrosis

Background: Renal fibrosis is a common pathophysiological feature of chronic kidney disease. Acute kidney injury (AKI) is defined as an independent causal factor of chronic kidney disease, with a pathological representation of post renal fibrosis. However, the etiopathogenesis underlying post renal fibrosis induced by AKI is not completely understood. Methods: BALB/c mice were treated with bpv or vehicle controls and were, respectively, the ischemia reperfusion (IR) model group and control group. All of the animals had blood taken from the orbital venous plexus at 24 hours after IR. Six mice in each group were randomly chosen and euthanized 7 days after IR treatment, and the remaining six mice in each group were euthanized 14 days after IR treatment. We examined the effect on post kidney fibrosis of inhibiting PTEN activity in mice in an IR induced AKI experimental model. Results: Compared with vehicle mice, bpv-(PTEN specific inhibitor) treated mice accumulated more bone marrow-derived fibroblasts and myofibroblasts in the kidneys. Inhibition of PTEN activity increased the expression of α-smooth muscle actin and extracellular matrix proteins and post kidney fibrosis. Furthermore, inhibition of PTEN activity resulted in more inflammatory cytokines in the kidneys of mice subjected to IR-induced renal fibrosis. Moreover, inhibition of PTEN activity up-regulated PI3K protein expression and Akt phosphorylation. Conclusions: Our study demonstrated that PTEN played an important role in post renal fibrosis in mice with ischemia reperfusion-induced AKI. These results indicated that the PTEN/PI3K/Akt signaling pathway may serve as a novel therapeutic target for AKI-induced chronic kidney disease.

scholarly journals UT-A1/A3 knockout mice show reduced fibrosis following unilateral ureteral obstruction

2020 ◽  
Vol 318 (5) ◽  
pp. F1160-F1166
Author(s):  
Fitra Rianto ◽  
Akihiro Kuma ◽  
Carla L. Ellis ◽  
Faten Hassounah ◽  
Eva L. Rodriguez ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Growth Factor ◽  
Kidney Disease ◽  
Knockout Mice ◽  
Ureteral Obstruction ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Unilateral Ureteral Obstruction

Renal fibrosis is a major contributor to the development and progression of chronic kidney disease. A low-protein diet can reduce the progression of chronic kidney disease and reduce the development of renal fibrosis, although the mechanism is not well understood. Urea reabsorption into the inner medulla is regulated by inner medullary urea transporter (UT)-A1 and UT-A3. Inhibition or knockout of UT-A1/A3 will reduce interstitial urea accumulation, which may be beneficial in reducing renal fibrosis. To test this hypothesis, the effect of unilateral ureteral obstruction (UUO) was compared in wild-type (WT) and UT-A1/A3 knockout mice. UUO causes increased extracellular matrix associated with increases in transforming growth factor-β, vimentin, and α-smooth muscle actin (α-SMA). In WT mice, UUO increased the abundance of three markers of fibrosis: transforming growth factor-β, vimentin, and α-SMA. In contrast, in UT-A1/A3 knockout mice, the increase following UUO was significantly reduced. Consistent with the Western blot results, immunohistochemical staining showed that the levels of vimentin and α-SMA were increased in WT mice with UUO and that the increase was reduced in UT-A1/A3 knockout mice with UUO. Masson’s trichrome staining showed increased collagen in WT mice with UUO, which was reduced in UT-A1/A3 knockout mice with UUO. We conclude that reduced UT activity reduces the severity of renal fibrosis following UUO.

Fate alteration of bone marrow-derived macrophages ameliorates kidney fibrosis in murine model of unilateral ureteral obstruction

2018 ◽  
Vol 34 (10) ◽  
pp. 1657-1668 ◽  
Author(s):  
Ying Yang ◽  
Xiaojian Feng ◽  
Xinyan Liu ◽  
Ying Wang ◽  
Min Hu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Ureteral Obstruction ◽  
Renal Fibrosis ◽  
Kidney Diseases ◽  
Unilateral Ureteral Obstruction ◽  
Immunofluorescent Staining ◽  
Enzyme Linked Immunosorbent Assay ◽  
Pathological Feature ◽  
Kidney Fibrosis ◽  
Anti Inflammatory

AbstractBackgroundRenal fibrosis is a key pathological feature and final common pathway leading to end-stage kidney failure in many chronic kidney diseases. Myofibroblast is the master player in renal fibrosis. However, myofibroblasts are heterogeneous. Recent studies show that bone marrow-derived macrophages transform into myofibroblasts by transforming growth factor (TGF)-β-induced macrophage–myofibroblast transition (MMT) in renal fibrosis.MethodsTGF-β signaling was redirected by inhibition of β-catenin/T-cell factor (TCF) to increase β-catenin/Foxo in bone marrow-derived macrophages. A kidney fibrosis model of unilateral ureteral obstruction was performed in EGFP bone marrow chimera mouse. MMT was examined by flow cytometry analysis of GFP+F4/80+α-SMA+ cells from unilateral ureteral obstruction (UUO) kidney, and by immunofluorescent staining of bone marrow-derived macrophages in vitro. Inflammatory and anti-inflammatory cytokines were analysis by enzyme-linked immunosorbent assay.ResultsInhibition of β-catenin/TCF by ICG-001 combined with TGF-β1 treatment increased β-catenin/Foxo1, reduced the MMT and inflammatory cytokine production by bone marrow-derived macrophages, and thereby, reduced kidney fibrosis in the UUO model.ConclusionsOur results demonstrate that diversion of β-catenin from TCF to Foxo1-mediated transcription not only inhibits the β-catenin/TCF-mediated fibrotic effect of TGF-β, but also enhances its anti-inflammatory action, allowing therapeutic use of TGF-β to reduce both inflammation and fibrosis at least partially by changing the fate of bone marrow-derived macrophages.

scholarly journals Daily Low-intensity Pulsed Ultrasound Ameliorates Renal Fibrosis and Inflammation in Experimental Hypertensive and Diabetic Nephropathy

Hypertension ◽  
2020 ◽  
Vol 76 (6) ◽  
pp. 1906-1914
Author(s):  
Yoshiki Aibara ◽  
Ayumu Nakashima ◽  
Ki-ichiro Kawano ◽  
Farina Mohamad Yusoff ◽  
Fumitaka Mizuki ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Renal Failure ◽  
Diabetic Nephropathy ◽  
Angiotensin Ii ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Pulsed Ultrasound ◽  
Hypertensive Nephropathy ◽  
Low Intensity Pulsed Ultrasound ◽  
Low Intensity

The estimated morbidity rate of chronic kidney disease is 8% to 16% worldwide, and many patients with chronic kidney disease eventually develop renal failure. Thus, the development of new therapeutic strategies for preventing renal failure is crucial. In this study, we assessed the effects of daily low-intensity pulsed ultrasound (LIPUS) therapy on experimental hypertensive nephropathy and diabetic nephropathy. Unilateral nephrectomy and subcutaneous infusion of angiotensin II via osmotic mini-pumps were used to induce hypertensive nephropathy in mice. Immunohistochemistry revealed that daily LIPUS treatment ameliorated renal fibrosis and infiltration of inflammatory cells induced by angiotensin II. A similar therapeutic effect was also observed in mice with angiotensin II-induced hypertensive nephropathy in which splenectomy was performed. In addition, LIPUS treatment significantly decreased systolic blood pressure after 21 days. Subsequently, db/db mice with unilateral nephrectomy developed proteinuria; daily LIPUS treatment significantly reduced proteinuria after 42 days. In addition, immunohistochemistry revealed that renal fibrosis was significantly ameliorated by LIPUS treatment. Finally, LIPUS stimulation suppressed TGF-β1 (transforming growth factor-β1)-induced phosphorylation of Smad2 and Smad3 in HK-2 (human proximal tubular cell line) cells. LIPUS treatment may be a useful therapy for preventing the progression of renal fibrosis in patients with chronic kidney disease.

scholarly journals P0690CORRELATIONS BETWEEN OPG/RANKL/RANK AXIS, VITAMIN D STATUS, PTH AND VASCULAR CALCIFICATION IN AN ADENINE-INDUCED MODEL OF CHRONIC KIDNEY DISEASE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Beata Sieklucka ◽  
Tomasz Domaniewski ◽  
Marta Zieminska ◽  
Malgorzata Galazyn-Sidorczuk ◽  
Anna Pawlak ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Kidney Disease ◽  
Uric Acid ◽  
Kidney Disease ◽  
Vascular Calcification ◽  
Control Group ◽  
Urea Nitrogen ◽  
And Control ◽  
Rank Gene

Abstract Background and Aims Chronic kidney disease (CKD) is a major public health problem worldwide and refers to a wide range of disorders in bone and mineral metabolism, abnormalities of biochemical parameters and pathological calcification of the blood vessels. Vascular calcification (VC) is a common complication in CKD patients, contributes to cardiovascular disease (CVD), and associates with increased mortality and morbidity. The precise mechanism of VC in CKD is not yet fully understood. Recently discovered molecules such as osteoprotegerin (OPG), its ligand receptor activator of nuclear factor NF-κB ligand (RANKL) and RANK are not only well-known to play a crucial role in bone homeostasis, but they has also been implicated in the process of development of vascular complications However the exact role of OPG/RANKL/RANK axis in the process of VC has not been yet fully assessed. Thus, the aim of this work is to evaluate the role of OPG/RANKL/RANK axis in the process of calcification in CKD. Method Seventy two male Wistar rats weighing 260-290 g (8-weeks old) were initially divided into 6 groups containing 12 animals in each group. Rats were divided into six groups: control rats (K4, K6, K8) and CKD rats (B4, B6, B8). Control group rats received standard diet, whereas CKD rats were fed a low adenine – diet containing 0.3 % adenine, 1.0 % Ca, 1.2 % Pi through 4 (K4, B4), 6 (K6, B6) and 8 (K8, B8) weeks. Subsequently, CKD and control rats were sacrificed at weeks 4 (n=24), 6 (n=24) and 8 (n=24). One day before being killed, the rats were placed in metabolic cages for 24-hour urine collection. Thereafter, the rats were anesthetized and samples of blood, as well as aortas were collected. Next, the OPG, RANKL, parathyroid hormone (PTH), 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxy vitamin D3 1,25(OH)2D3 concentrations were determined using appropriate ELISA kits. Then the sRANKL/OPG ratio was calculated. The OPG, RANK and RANKL gene expression was assessed using real-time PCR (RT-PCR). The VC was quantified by measurement of the arterial calcium (Ca) and phosphate (Pi) content using flame atomic absorption. Serum levels of urea nitrogen, creatinine, uric acid, Ca, Pi and urinary levels of creatinine, Ca and Pi were measured. Results There was a progressive increase in serum urea nitrogen, creatinine, uric acid and PTH of CKD rats in comparison to control values. We also observed significantly decreased levels of 25(OH)D, 1,25(OH)2D and serum Ca. Total Ca content in the aorta was significantly increased in CKD rats in comparison with control group, whereas total Pi content in the aorta was significantly increased only in B8 group in comparison to appropriate controls. There were no differences in serum OPG and sRANKL levels between CKD and control rats. In contrast, we observed decreased OPG, RANKL and RANK gene expression in a B4 group in comparison to appropriate controls, whereas in a B6 group we noticed increased OPG, RANKL and decreased RANK gene expression. B8 group revealed increased RANKL and RANK gene expression, but there were no differences in OPG gene expression between CKD rats and control group. Furthermore, we observed positive correlations between serum sRANKL and OPG and RANK gene expression. Ca and P content in the aorta inversely corelated with RANKL gene expression, whereas positively with OPG gene expression. Serum 25(OH)D concentrations correlated inversely with Ca in aorta. PTH was positively correlated with serum RANKL and OPG and gene expression these cytokines. Conclusion Our results suggest that OPG/RANK/RANKL axis may be involved in the process of vascular calcification in chronic kidney disease. However, its role and evaluation of precise mechanism in this field requires further evaluation.

scholarly journals Coagulation profile in two nephropathic dogs

2021 ◽  
Vol 52 (4) ◽  
Author(s):  
Anjaly M. V. ◽  
Sindhu K. R. ◽  
Usha N. P. ◽  
Ajithkumar S. ◽  
Justin Davis K
Keyword(s):  
Chronic Kidney Disease ◽  
Renal Failure ◽  
Kidney Disease ◽  
Renal Dysfunction ◽  
Partial Thromboplastin Time ◽  
Bleeding Time ◽  
Activated Partial Thromboplastin Time ◽  
Acute Renal Dysfunction ◽  
Coagulation Profile ◽  
D Dimer

Coagulatory abnormalities are common in renal dysfunction in humans. The studies on coagulatory abnormalities in renal failure in dogs are limited. The present paper deals with coagulation profile in acute and chronic kidney disease in dogs. The haemostatic defects observed in acute renal dysfunction included thrombocytopaenia, prolonged capillary bleeding time (CBT), elevated D-Dimer and hypoantithrombinemia which indicated a hypercoagulable state. Prolongation of prothrombin time (PT), activated partial thromboplastin time (aPTT), elevated D-Dimer concentration and hypoantithrombinemia in chronic kidney disease indicated the presence of hypocoagulable state

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