scholarly journals Involvement of Circulating Exosomal MicroRNAs in Jian-Pi-Yi-Shen Formula Protection Against Adenine-Induced Chronic Kidney Disease

2021 ◽  
Vol 11 ◽  
Author(s):  
Xinhui Liu ◽  
Siqi Liu ◽  
Denggui Luo ◽  
Shiying Huang ◽  
Fochang Wang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Rna Sequencing ◽  
Rat Model ◽  
Small Rna ◽  
Serum Biochemistry ◽  
Small Rna Sequencing ◽  
Sprague Dawley ◽  
Exosomal Mirnas ◽  
Serum Exosomes

Jian-Pi-Yi-Shen formula (JPYSF) is a traditional Chinese medicine (TCM) formula used in clinic to treat chronic kidney disease (CKD) for decades. However, the mechanisms of JPYSF in treating CKD have not been fully elucidated. The aim of the present study was to test the renoprotective effect of JPYSF on CKD rat model and investigate the potential mechanism from the perspective of serum exosomal microRNAs (miRNAs). CKD rat model was induced by feeding Sprague-Dawley rats a diet containing 0.75% w/w adenine for four weeks. The rats in the treatment group were given 10.89 g/kg JPYSF by gavage every day, starting from the 3rd week of the adenine-containing diet for six weeks. Serum biochemistry and histopathology were used to evaluate the renoprotective effects of JPYSF. Serum exosomes were isolated by ExoQuick-TC PLUS exosomes extraction kit and were identified by transmission electron microscopy, nanoparticle tracking analysis, and western blot. Exosomal miRNAs profiling was analyzed by small RNA sequencing. The results showed that JPYSF treatment significantly lowered serum creatinine and blood urea nitrogen levels and alleviated renal pathological injury in CKD rats. Furthermore, serum exosomes were successfully isolated and identified. Small RNA sequencing revealed that 4 exosomal miRNAs (miR-192-5p, miR-194-5p, miR-802-5p, and miR-143-3p) were significantly downregulated in the CKD group and were markedly upregulated after JPYSF treatment. At last, miR-192-5p was identified as the most relevant miRNA for CKD diagnosis and JPYSF treatment. In conclusion, JPYSF protects kidney from adenine-induced CKD, which may be associated with modulation of exosomal miRNAs.

scholarly journals Dietary Phosphorus Differentially Alters Uremic Toxin Production in a Rat Model of Chronic Kidney Disease

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 843-843
Author(s):  
Dennis Cladis ◽  
Kendal Schmitz ◽  
Amber Jannasch ◽  
Bruce Cooper ◽  
Kathleen Hill Gallant
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Rat Model ◽  
Kidney Tissue ◽  
Toxin Production ◽  
Sham Operation ◽  
Uremic Toxin ◽  
Sprague Dawley ◽  
Waste Products ◽  
Dietary Phosphorus

Abstract Objectives Chronic kidney disease (CKD) is characterized by declining kidney function, limiting the kidney's ability to efficiently remove metabolic waste products from circulation. Byproducts of gut microbial protein metabolism, termed uremic retention solutes (URS), accumulate in CKD patients and are associated with accelerating kidney decline. The gut microbes responsible for generating URS are dependent upon phosphorus (P) for growth and survival. As dietary P restriction is a cornerstone of CKD treatment, we hypothesized that changes in dietary P loads would alter URS production. Methods To evaluate this, 8-week-old male Sprague Dawley rats underwent 5/6th nephrectomy (Nx, n = 24) or sham operation (n = 20) and were maintained on a 0.6% P diet (w/w) for three weeks. Animals were then randomized to receive either low (0.1% (w/w)) or high (1.2% (w/w)) P diets for 4h/d for 7d. Blood was collected at the start and end of the 7d diet (baseline and sacrifice, respectively). Serum was analyzed for blood urea nitrogen (BUN) and URS, including trimethylamine oxide (TMAO), indoxyl sulfate (IS), and p-cresol sulfate (pCS), via LC-MS. Results Nx rats had significantly elevated BUN compared to sham controls (38.9 ± 5.9 vs 23.1 ± 5.1 mg/dL, p < 0.0001). Additionally, the presence of significantly enlarged kidney tissue in Nx animals verified the progression of kidney decline. At sacrifice, all URS were elevated in Nx animals as compared to sham controls (p < 0.0001), though changes in dietary P loads only affected IS production (low vs. high, p = 0.0003). When comparing baseline to sacrifice, TMAO decreased, IS remained consistent, and pCS increased in all rats. Conclusions Our results indicate that dietary P loads may differentially affect the production of some URS in a rat model of CKD. As dietary P restriction is one of the cornerstones of CKD treatment, we posit that this dietary strategy influences URS production, CKD progression, and, ultimately, health outcomes. Funding Sources ASBMR, NIH K01.

scholarly journals Identification of exosomal miRNA biomarkers for diagnosis of papillary thyroid cancer by small RNA sequencing

2020 ◽  
Vol 182 (1) ◽  
pp. 111-121 ◽  
Author(s):  
Daofeng Dai ◽  
Yawen Tan ◽  
Liangfeng Guo ◽  
Aifa Tang ◽  
Yongsheng Zhao
Keyword(s):  
Thyroid Cancer ◽  
Rna Sequencing ◽  
Small Rna ◽  
Thyroid Nodules ◽  
Small Rna Sequencing ◽  
Papillary Thyroid ◽  
Exosomal Mirnas ◽  
Exosomal Mirna ◽  
Benign Thyroid Nodules ◽  
Benign Thyroid

Context Exosomal miRNAs are considered potential non-invasive biomarkers for thyroid cancer. However, the global exosomal miRNAs profile for papillary thyroid cancer (PTC) has not been revealed. Objective This study investigated the diagnostic value of plasma and serum exosomal miRNAs for PTC. Methods Plasma and serum samples were collected from ten patients with benign thyroid nodules and 17 with PTC for small RNA sequencing. Plasma samples were collected from two independent cohorts, including 119 patients with PTC, 51 healthy people and 82 patients with benign thyroid nodules, for validation by quantitative reverse-transcription polymerase chain reaction (RT-qPCR). Results Small RNA sequencing identified 41 putative exosomal miRNA biomarkers for PTC. Twelve miRNAs were selected for validation. miR-376a-3p, miR-4306, miR-4433a-5p, and miR-485-3p expression significantly increased in patients with PTC compared to that in healthy people and patients with benign thyroid nodules (P ˂ 0.05). Moreover, miR-485-3p and miR-4433a-5p presented larger areas under the curve (AUCs). The high expression of exosomal miR-485-3p correlated with tumor size greater than or equal to 1 cm, advanced clinical stage, extrathyroidal extension, BRAF mutation, and lymph node metastasis. Besides, miR-485-3p exhibited the highest AUCs in diagnosing PTC patients with high-risk factors. Conclusions Plasma exosomal miR-485-3p and miR-4433a-5p might serve as biomarkers for PTC diagnosis. Plasma exosomal miR-485-3p could enable discrimination between high-risk and low-risk PTC.

scholarly journals A dual blocker of endothelin A/B receptors mitigates hypertension but not renal dysfunction in a rat model of chronic kidney disease and sleep apnea

2019 ◽  
Vol 316 (5) ◽  
pp. F1041-F1052 ◽  
Author(s):  
Humberto Morales-Loredo ◽  
David Jones ◽  
Adelaeda Barrera ◽  
Perenkita J. Mendiola ◽  
Joshua Garcia ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Sleep Apnea ◽  
Kidney Disease ◽  
Renal Dysfunction ◽  
Rat Model ◽  
Sprague Dawley ◽  
Arterial Blood ◽  
Sprague Dawley Rats ◽  
Obstructive Sleep ◽  
End Stage

Obstructive sleep apnea is characterized by recurrent episodes of pharyngeal collapse during sleep, resulting in intermittent hypoxia (IH), and is associated with a high incidence of hypertension and accelerated renal failure. In rodents, endothelin (ET)-1 contributes to IH-induced hypertension, and ET-1 levels inversely correlate with glomerular filtration rate in patients with end-stage chronic kidney disease (CKD). Therefore, we hypothesized that a dual ET receptor antagonist, macitentan (Actelion Pharmaceuticals), will attenuate and reverse hypertension and renal dysfunction in a rat model of combined IH and CKD. Male Sprague-Dawley rats received one of three diets (control, 0.2% adenine, and 0.2% adenine + 30 mg·kg−1·day−1macitentan) for 2 wk followed by 2 wk of recovery diet. Rats were then exposed for 4 wk to air or IH (20 short exposures/h to 5% O2-5% CO27 h/day during sleep). Macitentan prevented the increases in mean arterial blood pressure caused by CKD, IH, and the combination of CKD + IH. However, macitentan did not improve kidney function, fibrosis, and inflammation. After CKD was established, rats were exposed to air or IH for 2 wk, and macitentan feeding continued for 2 more wk. Macitentan reversed the hypertension in IH, CKD, and CKD + IH groups without improving renal function. Our data suggest that macitentan could be an effective antihypertensive in patients with CKD and irreversible kidney damage as a way to protect the heart, brain, and eyes from elevated arterial pressure, but it does not reverse toxin-induced tubule atrophy.

Abstract P125: RNA Sequencing of Left-ventricular Tissue Highlights Novel Pathways Impacted by the Loss of miR-146b-5p in a Rat Model of Chronic Kidney Disease

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Mark R Paterson ◽  
Pengyuan Liu ◽  
Alison J Kriegel
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Rna Sequencing ◽  
Rat Model ◽  
Fold Increase ◽  
Left Ventricular ◽  
Signaling Networks ◽  
Negative Feedback Regulation ◽  
Altered Expression ◽  
Cardiovascular Tissue

Chronic kidney disease (CKD) mediates pathological changes in heart and vascular tissues, yet many molecular mechanisms by which renal injury directly affects cardiovascular pathology (CVD) are unknown. miRNAs are proposed to be powerful regulators of pathophysiological signaling networks; having the potential to radically change the landscape of mRNA transcript expression and protein abundance in the context of health and disease. We have profiled the expression of miRNAs in a rat model of CKD – the 5/6 nephrectomy (5/6Nx) – with the objective to identify miRNAs with strong effects on CKD-mediated CVD. One such miRNA, miR-146b-5p (miR-146b), is highly upregulated in 5/6Nx rats compared to sham-operated controls at 7-weeks post-5/6Nx in both the kidney (5.4 fold increase; p<0.05) and the heart (1.6 fold increase, p<0.05), a time-point at which we see maximal renal and cardiac pathology. To examine the effects of miR-146b upregulation in our model of CKD, we performed RNA sequencing on cardiac tissue at 7 weeks post-5/6Nx in both wild-type (WT) Sprague-Dawley (SD) rats and a unique CRISPR-Cas9-mediated miR-146b knockout strain (miR-146b -/- ) created on the SD background. Of 3,018 genes differentially regulated by more than 1.5-fold (absolute value) in miR-146b -/- vs. WT rats after 5/6Nx, 135 had significantly altered expression (adjusted p-value <0.05). We filtered all differentially expressed genes through Ingenuity Pathway Analysis to identify affected signaling networks in miR-146b -/- vs. WT rats that correlate with observed pathological phenotypes. The expression pattern of differentially regulated genes in these networks indicates predicted activation of pathways that contribute to tissue fibrosis and mineralization, reactive oxygen species signaling, and the inflammatory and immune responses. These pathways are enriched with predicted miR-146b target genes and correlate closely with observed phenotypes in miR-146b -/- 5/6Nx rats; including increased renal fibrosis and mineralization of cardiovascular tissue, and the well-known role of miR-146b in negative feedback regulation of NFκB signaling. These preliminary analyses uncover unique networks of genes regulated by miR-146b that may contribute to CKD-mediated CVD.

Contribution of volume overload to progression of cardiovascular disease in a rat model of chronic kidney disease

2018 ◽  
Vol 96 (12) ◽  
pp. 1197-1208
Author(s):  
Manal Moustafa Mahmoud ◽  
Asmaa Mohammed Shamseldeen ◽  
Laila Ahmed Rashed ◽  
Amal Elham Fares ◽  
Ashraf Shamaa ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Rat Model ◽  
Volume Overload ◽  
High Salt ◽  
Sham Operation ◽  
Sprague Dawley ◽  
High Salt Diet ◽  
Sprague Dawley Rats ◽  
Cardiac Functions

Volume overload is a common phenomenon in patients with chronic kidney disease that is associated with cardiovascular risk factors. However, its contribution to the development of adverse cardiovascular outcomes in those patients is not fully understood. Thus, the present work investigated the effect of salt-induced volume overload on cardiac functions and geometry in a rat model of chronic kidney disease. Thirty adult male Sprague–Dawley rats were randomly divided. One set of animals received a sham operation, while another set of animals underwent uninephrectomy. Rats were then fed either a normal-salt (0.4%) or high-salt (8.0%) diet for 6 weeks. The salt-loaded, uninephrectomized rats were treated with indapamide (3 mg·kg–1·day–1, orally) for 6 weeks. We found that uninephrectomized rats subjected to a high-salt diet (8.0%) for 6 weeks presented with hypertension, proteinuria, decreased renal Klotho expression, and deterioration in cardiac hemodynamics and histology. Echocardiography to assess cardiac function showed that ejection fraction and fractional shortening were positively correlated with relative renal Klotho expression. In conclusion, salt-induced volume overload in a rat model of chronic kidney disease has an adverse cardiovascular outcome and is associated with inflammatory activation and decrease in renal Klotho expression.

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