Protective effects of Rho kinase inhibitor fasudil on rats with chronic kidney disease

2013 ◽  
Vol 304 (11) ◽  
pp. F1325-F1334 ◽  
Author(s):  
Taketoshi Kushiyama ◽  
Takashi Oda ◽  
Kojiro Yamamoto ◽  
Keishi Higashi ◽  
Atsushi Watanabe ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Low Dose ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
High Dose ◽  
Protective Effects ◽  
Treatment Groups ◽  
Rho Kinase Inhibitor ◽  
Group A

The protective effects of Rho kinase inhibitor fasudil against renal diseases have recently been reported. We compared the therapeutic effects of fasudil on the spontaneously hypercholesterolemic (SHC) rat, a model of chronic kidney disease (CKD) with proteinuria, with those of the angiotensin receptor blocker olmesartan (OL) by paying attention to the proteinuria and the macrophage phenotype. SHC rats were allocated to six treatment groups: a vehicle (Ve) group, a low-dose fasudil (FL) group, a high-dose fasudil (FH) group, an OL group, a combination of low-dose fasudil and OL (CL) group, and a combination of high-dose fasudil and OL (CH) group. Sprague-Dawley rats treated with vehicle served as a control ( n = 7/each). The rats were treated for 24 wk. Compared with the Ve group, proteinuria was significantly decreased in the FH, OL, and CL groups, and it completely disappeared in the CH group. Glomerular stainings of nephrin and F-actin were focally impaired in the Ve group but were restored in the CH group. Western blotting showed that the CH group had significantly increased renal nephrin expression compared with the Ve group. Interstitial infiltration of macrophages was significantly increased in the Ve group, which was significantly attenuated in all treatment groups. The ratio of CD206 (M2 macrophage marker) to CD68 mRNA was significantly greater in the CH group than in the Ve group. These results indicate that fasudil with OL reduces proteinuria by protecting podocyte integrity and alters the interstitial macrophage density/phenotype, thereby exerting renoprotective effects against CKD.

scholarly journals Modulatory Effect of Fermented Papaya Extracts on Mammary Gland Hyperplasia Induced by Estrogen and Progestin in Female Rats

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Zhenqiang You ◽  
Junying Sun ◽  
Feng Xie ◽  
Zhiqin Chen ◽  
Sheng Zhang ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Oxidative Dna Damage ◽  
Mammary Glands ◽  
Estradiol Benzoate ◽  
Female Rats ◽  
Control Group ◽  
High Dose ◽  
Protective Effects ◽  
Treatment Groups ◽  
Group A

Fermented papaya extracts (FPEs) are obtained by fermentation of papaya by Aspergillus oryzae and yeasts. In this study, we investigated the protective effects of FPEs on mammary gland hyperplasia induced by estrogen and progestogen. Rats were randomly divided into 6 groups, including a control group, an FPE-alone group, a model group, and three FPE treatment groups (each receiving 30, 15, or 5 ml/kg FPEs). Severe mammary gland hyperplasia was induced upon estradiol benzoate and progestin administration. FPEs could improve the pathological features of the animal model and reduce estrogen levels in the serum. Analysis of oxidant indices revealed that FPEs could increase superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, decrease malondialdehyde (MDA) level in the mammary glands and serum of the animal models, and decrease the proportion of cells positive for the oxidative DNA damage marker 8-oxo-dG in the mammary glands. Additionally, estradiol benzoate and progestin altered the levels of serum biochemical compounds such as aspartate transaminase (AST), total bilirubin (TBIL), and alanine transaminase (ALT), as well as hepatic oxidant indices such as SOD, GSH-Px, MDA, and 8-oxo-2′-deoxyguanosine (8-oxo-dG). These indices reverted to normal levels upon oral administration of a high dose of FPEs. Taken together, our results indicate that FPEs can protect the mammary glands and other visceral organs from oxidative damage.

Protective Effects of a Rho Kinase Inhibitor on Paraquat-Induced Acute Lung Injuries in Rats

Inflammation ◽  
2018 ◽  
Vol 41 (6) ◽  
pp. 2171-2183 ◽  
Author(s):  
Lichun Zhang ◽  
Qiuhe Li ◽  
Zhenning Liu ◽  
Wei Liu ◽  
Min Zhao
Keyword(s):  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Protective Effects ◽  
Rho Kinase Inhibitor ◽  
Lung Injuries

scholarly journals Cyclophilin D Promotes Acute, but Not Chronic, Kidney Injury in a Mouse Model of Aristolochic Acid Toxicity

Toxins ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 700
Author(s):  
Khai Gene Leong ◽  
Elyce Ozols ◽  
John Kanellis ◽  
Frank Y. Ma ◽  
David J. Nikolic-Paterson
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Cell Death ◽  
Kidney Disease ◽  
Low Dose ◽  
Aristolochic Acid ◽  
Chinese Herb ◽  
Kidney Injury ◽  
High Dose ◽  
Cyclophilin D

The plant-derived toxin, aristolochic acid (AA), is the cause of Chinese Herb Nephropathy and Balkan Nephropathy. Ingestion of high dose AA induces acute kidney injury, while chronic low dose ingestion leads to progressive kidney disease. Ingested AA is taken up by tubular epithelial cells of the kidney, leading to DNA damage and cell death. Cyclophilin D (CypD) participates in mitochondrial-dependent cell death, but whether this mechanism operates in acute or chronic AA-induced kidney injury is unknown. We addressed this question by exposing CypD-/- and wild type (WT) mice to acute high dose, or chronic low dose, AA. Administration of 5 mg/kg AA to WT mice induced acute kidney injury 3 days later, characterised by loss of kidney function, tubular cell damage and death, and neutrophil infiltration. All of these parameters were significantly reduced in CypD-/- mice. Chronic low dose (2 mg/kg AA) administration in WT mice resulted in chronic kidney disease with impaired renal function and renal fibrosis by day 28. However, CypD-/- mice were not protected from AA-induced chronic kidney disease. In conclusion, CypD facilitates AA-induced acute kidney damage, but CypD does not contribute to the transition of acute kidney injury to chronic kidney disease during ongoing AA exposure.

Transcriptomic Signatures of Exacerbated Progression in Leptospirosis Subclinical Chronic Kidney Disease with Secondary Nephrotoxic Injury

2021 ◽  
Author(s):  
Li-Fang Chou ◽  
TingWen Chen ◽  
Huan-Yu Yang ◽  
Ya-Chung Tian ◽  
Ming-Yang Chang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Topoisomerase Ii ◽  
Low Dose ◽  
Expression Patterns ◽  
Kidney Injury ◽  
Differentially Expressed ◽  
High Dose ◽  
Integrin Linked Kinase ◽  
Topoisomerase Ii Α

High-incidence regions of Leptospirosis caused by Leptospira spp., coincide with chronic kidney disease. This study investigates whether asymptomatic leptospirosis is an emerging culprit that predispose to progressive chronic kidney disease when superimposed on secondary nephrotoxic injury. Kidney histology/function and whole-transcriptomic profiles were evaluated for leptospira-infected C57/BL6 mice with adenine-induced kidney injury. The extent of tubulointerstitial kidney lesions and the expression of inflammation/fibrosis genes in infected mice with low-dose (0.1%) adenine, particularly in high-dose (0.2%) adenine-fed superimposed on leptospira-infected mice, were significantly increased compared with mice following infection or adenine diet alone and the findings are consistent with renal transcriptome analysis. Pathway enrichment findings showed integrin β- and fibronectin-encoding genes had distinct expression within the integrin-linked kinase signaling pathway which were up-regulated in 0.2% adenine-fed leptospira-infected mice but not in 0.2% adenine-fed mice, indicating background subclinical leptospiral infection indeed enhanced subsequent secondary nephrotoxic kidney injury and potential pathogenic molecules associated with secondary nephrotoxic leptospirosis. Comparative analysis of gene-expression patterns with UUO-induced mouse renal fibrosis and patients with chronic kidney disease showed that differentially expressed orthologous genes such as hemoglobin α, PDZ binding kinase and DNA topoisomerase II α were identified in infected mice fed with low-dose and high-dose adenine, respectively, revealing differentially expressed signatures identical to those found in the datasets and may serve as markers of aggravated kidney progression. This study indicates that background subclinical leptospirosis, when subjected to various degrees of subsequent secondary nephrotoxic injury, may predispose to exacerbated fibrosis, mimicking the pathophysiological process of progressive chronic kidney disease.

scholarly journals A Rho-kinase inhibitor, fasudil, prevents development of diabetes and nephropathy in insulin-resistant diabetic rats

2007 ◽  
Vol 192 (3) ◽  
pp. 595-603 ◽  
Author(s):  
Yuichi Kikuchi ◽  
Muneharu Yamada ◽  
Toshihiko Imakiire ◽  
Taketoshi Kushiyama ◽  
Keishi Higashi ◽  
...  
Keyword(s):  
Hemoglobin A1c ◽  
Kinase Inhibitor ◽  
Rho Kinase ◽  
Diabetic Rats ◽  
Serum Adiponectin ◽  
High Dose ◽  
Insulin Resistant ◽  
Oletf Rats ◽  
Rho Kinase Inhibitor

Fasudil, a Rho-kinase inhibitor, may improve insulin signaling. However, its long-term effect on metabolic abnormalities and its preventive effect on diabetic nephropathy are still unknown. We assessed these effects of fasudil in insulin-resistant diabetic rats, comparing them with those of an angiotensin II receptor blocker, olmesartan. Male Otsuka Long–Evans Tokushima fatty (OLETF) and Long–Evans Tokushima Otsuka, non-diabetic control, rats at 15 weeks of age were used. OLETF rats were randomized to receive a low or a high dose of fasudil or olmesartan for 25 weeks. To examine the therapeutic effects after the development of diabetes, OLETF rats at 30 weeks of age were given fasudil for 10 weeks. Administration of high-dose fasudil completely suppressed the development of diabetes, obesity, and dyslipidemia and increased serum adiponectin levels in OLETF rats. High-dose olmesartan also decreased hemoglobin A1c and increased serum adiponectin. There was a significant correlation between hemoglobin A1c and serum adiponectin or free fatty acid levels. The treatment with high-dose fasudil ameliorated proteinuria, glomerulosclerosis, renal interstitial fibrosis, and macrophage infiltration in OLETF rats. Olmesartan, even at the low dose, suppressed renal complications. The treatment with fasudil after the development of diabetes improved the metabolic abnormalities in OLETF rats, but could not suppress the progression of nephropathy. We conclude that the long-term treatment with fasudil prevents the development of diabetes, at least in part, by improving adipocyte differentiation in insulin-resistant diabetic rats. Early use of fasudil may prevent diabetic nephropathy.

Change in Hemoglobin with Androgen and Low Dose Erythropoietin Versus Erythropoietin Alone in Patients of Anemia of Chronic Kidney Disease

2021 ◽  
Vol 15 (11) ◽  
pp. 3296-3298
Author(s):  
Muhammad Abdul Azim Baig ◽  
Ishtiaq Alam ◽  
Faheem Usman Sulehri ◽  
Irfana Hassan ◽  
Aliya Jafri ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Low Dose ◽  
Operational Definition ◽  
P Value ◽  
Care Hospital ◽  
Significant Difference ◽  
Group A ◽  
The Mean ◽  
Group B

Objectives: To determine the mean rise in hemoglobin with androgen and low dose erythropoietin versus erythropoietin alone in patients of anemia of chronic kidney disease. Methodology: A randomized control trial was conducted at a tertiary care hospital between October 2019 to April 2020. Both male and female from age >17years to 70 years with anemia of CKD as per operational definition were included. Patients with a history of blood transfusion in the last three months. Patients already on Erythropoietin therapy or those with uncontrolled hypertension BP >190/105 mm Hg at the time of study were excluded. Relevant data including demographic details, baseline hemoglobin was noted. Patients were randomly assigned to group A or group B by lottery method. Patients in group A were given 100mg of androgen (Nandrolone Decanoate) intramuscularly once weekly plus low dose of erythropoietin (2000 units twice weekly) subcutaneously for 6 months and patients in group B were given standard dose of erythropoietin (4000 units twice weekly) subcutaneously for 6 months. Rise in hemoglobin was recorded as per operational definition. Follow up was ensured by taking telephone contact. Data was recorded on pre-designed proforma. Results: Mean Hb levels after treatment were calculated as 12.48+1.20 in Group-A and 11.12+1.32 in Group-B, p value was calculated as 0.0001 showing a significant difference between the two groups, comparison of mean increase in Hb levels after treatment were calculated as 3.0+0.09 in Group-A and 1.72+0.67 in Group-B, p value was calculated as 0.0001 showing a significant difference between the two groups. Conclusion: We concluded that there was significantly greater rise in the mean hemoglobin with androgen plus low dose erythropoietin as compared to erythropoietin alone in treatment of anemia of chronic kidney disease. Nevertheless, further large-scale and multi-center studies will be needed to further explore the long-term efficacy and adverse effects of androgens among patients of anemia of chronic kidney disease. Keywords: Chronic kidney disease, anemia, androgen and low dose erythropoietin versus erythropoietin alone, mean increase

Evaluation of hippocampus in rhesus monkeys after chronic (1-year) inhalation exposure to marijuana: I. Electron microscopy

1990 ◽  
Vol 48 (3) ◽  
pp. 398-399
Author(s):  
A.M. Andrews ◽  
S.W. Wilson ◽  
A.C. Scallet ◽  
S.F. Ali ◽  
J. Bailey ◽  
...  
Keyword(s):  
Synaptic Vesicles ◽  
Rhesus Monkeys ◽  
Low Dose ◽  
Inhalation Exposure ◽  
Synaptic Cleft ◽  
High Dose ◽  
Withdrawal Time ◽  
Treatment Groups ◽  
Ultrastructural Evidence ◽  
Male Rhesus

Exposure of rhesus monkeys (Macaca mulatta) to marijuana via inhalation or to intravenous delta-9-tetrahydrocannabinol (THC), reportedly caused ultrastructural evidence of increased synaptic width. Chronic marijuana smoke in a single rhesus monkey examined after a six month withdrawal time caused ultrastructure changes in the septal, hippocampal and amygdala regions; the synaptic cleft was widened, electron opaque material was found in the cleft and in the pre- and postsynaptic regions, with some clumping of the synaptic vesicles. The objective of our study was to assess neuropathological alterations produced by chronic inhalation of marijuana smoke.Nineteen male rhesus monkeys, 3-5 years of age and weighing 3-8 kg, were divided into four treatment groups: a) sham control, b) placebo smoke (7 days/ week) c) low dose marijuana (2 times/week with 5 days/week sham) and d) high dose marijuana (7 times/week). A smoke exposure consisted of smoke from one cigarette (2.6% THC) burned down to 10 mm butt length. Smoke was administered via smoke generator (ADL II, Arthur D. Little, Inc. Cambridge, MA) and nose-mouth only masks (local production) equipped with one-way valves.

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