Adenine-induced Chronic Renal Failure Research Articles

Galangin attenuates adenine-induced chronic renal failure by inhibiting transforming growth factor beta (TGF-β) expression

Introduction: Galangin (3,5,7 tri-hydroxy flavone), naturally active flavonoid is derived from the rhizomes of Alpinia officinarum is proven to be effective antioxidant, anti-inflammatory, anti-cancer. However, protective effects of galangin in chronic renal failure (CRF) is not explored. Objectives: This study is aimed to investigate the nephroprotective activity of galangin in adenine-induced CRF rats. Materials and Methods: Adenine induced rats were administered galangin 20 mg/kg and 40 mg/kg body weight (BW) serum renal and hepatic parameters, and renal antioxidant-lipid peroxidation parameters, histological studies were carried out. The mechanism of action was investigated by flow cytometry. Results: Galangin has normalized serum renal and hepatic parameters, reduced oxidative stress and lipid peroxidation. Histopathology confirms nephroprotection. The percentage number of cells expressing transforming growth factor beta (TGF-β) was reduced with galangin treatment. Conclusion: Galangin exerts nephroprotection in adenine induced CRF by inhibiting TGF-β expression.

Comparative pharmacokinetics of six bioactive components of Shen-Wu-Yi-Shen tablets in normal and chronic renal failure rats based on UPLC-TSQ-MS/MS

Ethnopharmacological relevanceShen-Wu-Yi-Shen tablets (SWYST), a Chinese patent medicine consisting of 12 herbal medicines, was formulated by a famous TCM nephrologist, Zou Yunxiang. It is clinically used to improve the symptoms of nausea, vomiting, poor appetite, dry mouth and throat, and dry stool in patients with chronic renal failure (CRF) accompanied by qi and yin deficiency, dampness, and turbidity. SWYST can reduce urea nitrogen, blood creatinine, and urinary protein loss, and increase the endogenous creatinine clearance rate. However, little is known about its pharmacokinetics. Aim of studyTo compare the pharmacokinetics of six bioactive components after oral administration of SWYST in normal and adenine-induced CRF rats. Materials and methodsA method based on ultra-performance liquid chromatography coupled with a triple-stage quadrupole mass spectrometer (UPLC-TSQ-MS/MS) was developed and validated to determine the six bioactive compounds (albiflorin, paeoniflorin, plantagoguanidinic acid, rhein, aloe-emodin, and emodin) in rat plasma. Rat plasma samples were prepared using protein precipitation. Chromatography was performed on an Agilent Eclipse Plus C18 column (3.0 × 50 mm, 1.8 μm) using gradient elution with a mobile phase composed of acetonitrile and water containing 0.1% (v/v) formic acid, while detection was achieved by electrospray ionization MS under the multiple selective reaction monitoring modes. After SWYST administration, rat plasma was collected at different time points, and the pharmacokinetic parameters of six analytes were calculated and analyzed based on the measured plasma concentrations. ResultsThe UPLC-TSQ-MS/MS method was fully validated for its satisfactory linearity (r ≥ 0.9913), good precisions (RSD <11.5%), and accuracy (RE: -13.4∼13.1%), as well as acceptable limits in the extraction recoveries, matrix effects, and stability (RSD <15%). In normal rats, the six analytes were rapidly absorbed (Tmax ≤ 2 h), and approximately 80% of their total exposure was eliminated within 10 h. Moreover, in normal rats, the AUC0-t and Cmax of albiflorin, plantagoguanidinic acid, and rhein exhibited linear pharmacokinetics within the dose ranges, while that of paeoniflorin is non-linear. However, in CRF rats, the six analytes exhibited reduced elimination and significantly different AUC or Cmax values. These changes may reflect a decreased renal clearance rate or inhibition of drug-metabolizing enzymes and transporters in the liver and gastrointestinal tract caused by CRF. ConclusionsA sensitive UPLC-TSQ-MS/MS method was validated and used to investigate the pharmacokinetics of SWYST in normal and CRF rats. This is the first study to investigate the pharmacokinetics of SWYST, and our findings elucidate the causes of their different pharmacokinetic behaviors in CRF rats. Furthermore, the results provide useful information to guide further research on the pharmacokinetic-pharmacodynamic correlation and clinical application of SWYST.

Synthesis and structural characterization of xylan acetate ester and its antinephritic effects in rats with experimental chronic kidney disease

Acetic acid has been shown to be effective in chronic kidney disease (CKD). However, it is a low-molecular-weight compound that allows it to be absorbed in the upper digestive tract so that it cannot function in colon. To overcome these deficiencies, an acetate-releasing xylan derivative, xylan acetate ester (XylA), was synthesized and selected in this study for its potential in the treatment of CKD. IR, NMR and HPGPC were used to characterize the structure of XylA and its antinephritic effects was evaluated in vivo. The results showed that acetate was successfully grafted onto the C-2 and C-3 positions of xylan and with a molecular weight at 69157 Da. XylA treatments could relieve the symptoms of CKD in an adenine-induced chronic renal failure (CRF) model and an adriamycin-induced focal segmental glomerulosclerosis (FSGS) model in SD rats. Further study indicated that XylA could upregulate the short-chain fatty acids (SCFAs) in vitro and vivo. Nevertheless, the relative abundance of Phascolarctobacterium in colon was increased after XylA treatment. XylA could upregulate G-protein-coupled receptor 41 (GPR41) expression, inhibit glomerular cell apoptosis and promoting proliferation. Our study expands the application of xylan and provides a new idea for the treatment of CKD with acetic acid.

Neoxanthin alleviates the chronic renal failure-induced aging and fibrosis by regulating inflammatory process.

Chronic renal failure (CRF) refers to progressive renal damage caused by chronic kidney diseases (CKD). Dialysis therapy and kidney transplantation are the important treatment for CRF. However, due to the limitation of conditions, they cannot be widely utilized. At present, the treatment of renal failure is a worldwide problem in clinic. Therefore, in the current study, we investigated the potential therapeutic effects of neoxanthin on CFR-caused aging and fibrosis. In this work, the effects of neoxanthin on CRF were studied using experimental techniques such as biochemistry, immunohistochemistry and molecular biology. In vitro, neoxanthin alleviated the aging and oxidative damage of kidney cells. In vivo, we found that Neoxanthin could alleviate adenine-induced CRF. Neoxanthin also inhibited CRF-caused renal aging, fibrosis, oxidative stress and inflammation. These findings indicate that neoxanthin could delay the progression of CRF and alleviate CRF-induced aging and fibrosis. Collectively, we found that neoxanthin shows good potential to inhibit CRF-caused kidney aging and fibrosis, suggesting that neoxanthin may be used as a drug (or a functional food) for the treatment of CRF-related diseases.

Effects of furosemide and tadalafil in both conventional and nanoforms against adenine-induced chronic renal failure in rats

BackgroundChronic renal failure (CRF) is a progressive loss of renal function that lead to reduced sodium filtration and inappropriate suppression of tubular reabsorption that ultimately leads to volume expansion. The aim of this study was to study the efficacy of furosemide and tadalafil nanoforms compared to conventional forms against adenine-induced CRF rat-model.MethodsAddition of 0.75% adenine to the diet of rats for 4 weeks gained general acceptance as a model to study kidney damage as this intervention mimicked most of the structural and functional changes seen in human chronic kidney disease Urine analysis, histopathological changes and immunohistochemical expression of caspase-3 and interleukin-1 beta (IL-1β) in renal tissues were performed.ResultsOur results showed that the combination of tadalafil and furosemide using conventional and nanoparticle formulations had better renoprotective effect than individual drugs. This was demonstrated by improvement of urinary, serum and renal tissue markers as indicative of organ damage. This was also reflected on the reduction of tubular expression of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL).Immunohistochemical studies showed that the deteriorated renal cellular changes indicated by increased expression of caspase-3 and IL-1β were greatly improved by the combined treatment particularly with the nanoforms.ConclusionsThe nanoforms of both furosemide and tadalafil had greater renopreventive effects compared with conventional forms against adenine-induced CRF in rats.

Effect of Bushen Qudu Decoction on TGF-β1/Smads signal transduction pathway in rats with chronic renal failure

Purpose: To study the impact of Bushen Qudu Decoction on renal function, renal tissue morphology and TGF-β1/Smads signal transduction pathway in adenine-induced chronic renal failure rats.Methods: 76 rats were assigned to normal group, model group, uremic clearance group, benazepil group, Bushen Qudu decoction gunshan A group and Bushen Qudu decoction Guiza group. Renal failure was induced in rats using intragastric administration of adenine for 30 days. The expressions of TGF-β1, Smad2, Smad3 and Smad6 were determined with immunohistochemistry. Real-time quantitative PCR was employed to assay the mRNA expression of TGF-β1 in each group, while protein expressions of Smad2, Smad3 and Smad6 were determined with western blot. The scores of glomerular and tubulointerstitial lesions in each group were obtained by histopathological examination.Results: Bushen Qudu decoction significantly reduced BUN and creatinine in rats with chronic renal failure; furthermore, it also lowered the protein expressions of TGF-β1 and SMAD2/3, but Smad6 protein, relative to control (p &lt; 0.05). The TGF-β1mRNA expression was down-regulated (p &lt; 0.05), relative to control group.Conclusion: Bushen Qudu decoction reduces renal interstitial fibrosis in rats and delays the progression of chronic renal failure by regulating TGF-β1/Smads signaling pathway. These findings provide some insight that should facilitate the development of new drugs that would delay the onset of chronic renal failure.

Stewed Rhubarb Decoction Ameliorates Adenine-Induced Chronic Renal Failure in Mice by Regulating Gut Microbiota Dysbiosis.

This study aimed to investigate the protective effect of Stewed Rhubarb (SR) decoction on chronic renal failure (CRF) through the regulation of gut microbiota. Using a CRF mouse model induced by a 0.2% adenine diet, we proved that SR decoction (2.0 g crude SR/kg) significantly reduced the levels of urea and creatinine in plasma of CRF mice, accompanied by the improvement of renal fibrosis and tubular atrophy, amelioration of inflammation, and inhibition of aquaporins damage. Also, SR decoction alleviated gut barrier damage, indicative of the elevated mRNA expression of intestinal mucins and tight junctions. By 16S rDNA sequencing, SR decoction reshaped the imbalanced gut microbiota in CRF mice by statistically reversing the abundance changes of a wide range of intestinal bacteria at family and genus levels, which further led to balance in the production of intestinal metabolites, including short-chain fatty acids (acetic acid, propionic acid, and valeric acid), indole, and bile acids (TUDCA and CDCA). Inversely, SR decoction failed to repress the occurrence of CRF in mice with gut microbiota depletion, confirming the essential role of gut microbiota in SR decoction-initiated protection against CRF. In summary, SR decoction can improve adenine-induced CRF in mice by remolding the structure of destructed gut microbiota community. Our findings shed light on the clinical application of SR decoction in nephropathy treatment.

Protective effect and mechanism of Shenkang injection on adenine-induced chronic renal failure in rats.

ABSTRACTPurpose:To investigate the protective effects of Shenkang injection (SKI) on adenine-induced chronic renal failure (CRF) in rat.Methods:Sprague Dawley rats were randomly divided into five groups: control, model, and SKI groups (5, 10, 20 mL/kg). Rats in model and SKI groups were treated with adenine i.g. at a dose of 150 mg/kg every day for 12 weeks to induce CRF. Twelve weeks later, SKI was administered to the rat i.p. for four weeks. The effects of SKI on kidney injury and fibrosis were detected.Results:SKI inhibited the elevation of the urine level of N-acetyl-b-D-glucosaminidase, kidney injury molecule-1, beta-2-microglobulin, urea protein in CRF rats. The serum levels of uric acid and serum creatinine increased and albumin decreased in the model group, which was prevented by SKI. SKI inhibited the release of inflammatory cytokines and increasing the activities of antioxidant enzymes in serum. SKI inhibited the expression of transforming growth factor-β1, vascular cell adhesion molecule 1, intercellular adhesion molecule 1, collagen I, collagen III, endothelin-1, laminin in kidney of CRF rats.Conclusions:SKI protected against adenine-induced kidney injury and fibrosis and exerted anti-inflammatory, and antioxidant effects in CRF rats.

Total flavonoids in Epimedium koreanum Nakai alleviated chronic renal failure via promoting AMPK activation.

Chronic renal failure (CRF) is a result of the progression of chronic kidney diseases (CKD), a global health problem with a high cost of treatment and no ideal therapy. The aim of this study is to evaluate the pharmacological efficacy of the total flavonoids in Epimedium koreanum Nakai (TFE), a dietary supplement, against CRF and to determine the mechanism of actions. An adenine-induced CRF rat model and a TGF-β1 induced human kidney proximal tubule epithelial (HK-2) cell based in vitro renal fibrosis model were established and used to evaluate TFE's efficacy. Renal hemodynamics, biochemical indexes, inflammatory cytokines, histopathology and the reactive oxygen species (ROS) levels were determined to evaluate the efficacy of TFE on CRF. NMR-based metabolomics, immunohistochemical (IHC) staining, immunofluorescence (IF) staining, quantitative real time-PCR (qRT-PCR) and western blotting were conducted to determine the mechanism. The results showed that TFE had a significant effect on CRF at 150 mg kg-1 d-1 and could significantly alleviate renal fibrosis in the animal model. Twelve potential biomarkers, which mainly involve energy metabolism pathways, for CRF were identified using the metabolomics approach. The mechanism study suggested that TFE regulated AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) and AMPK/silent information regulator 1 (SIRT1)/nuclear factor kappa-B (NF-κB) signaling pathways. Furthermore, the effect of TFE was inhibited by compound C in the in vitro experiment, which also confirmed the above conclusion.

Shenkang Injection and Its Three Anthraquinones Ameliorates Renal Fibrosis by Simultaneous Targeting IƙB/NF-ƙB and Keap1/Nrf2 Signaling Pathways.

Oxidative stress and inflammation are important and critical mediators in the development and progression of chronic kidney disease (CKD) and its complications. Shenkang injection (SKI) has been widely used to treat patients with CKD. Although the anti-oxidative and anti-inflammatory activity was involved in SKI against CKD, its bioactive components and underlying mechanism remain enigmatic. A rat model of adenine-induced chronic renal failure (CRF) is associated with, and largely driven by, oxidative stress and inflammation. Hence, we identified the anti-oxidative and anti-inflammatory components of SKI and further revealed their underlying mechanism in the adenine-induced CRF rats. Compared with control rats, the levels of creatinine, urea, uric acid, total cholesterol, triglyceride, and low-density lipoprotein cholesterol in serum were significantly increased in the adenine-induced CRF rats. However, treatment with SKI and its three anthraquinones including chrysophanol, emodin, and rhein could reverse these aberrant changes. They could significantly inhibit pro-fibrotic protein expressions including collagen I, α-SMA, fibronectin, and vimentin in the kidney tissues of the adenine-induced CRF rats. Of note, SKI and rhein showed the stronger inhibitory effect on these pro-fibrotic protein expressions than chrysophanol and emodin. Furthermore, they could improve dysregulation of IƙB/NF-ƙB and Keap1/Nrf2 signaling pathways. Chrysophanol and emodin showed the stronger inhibitory effect on the NF-κB p65 protein expression than SKI and rhein. Rhein showed the strongest inhibitory effect on p65 downstream target gene products including NAD(P)H oxidase subunits (p47phox, p67phox, and gp91phox) and COX-2, MCP-1, iNOS, and 12-LO in the kidney tissues. However, SKI and rhein showed the stronger inhibitory effect on the significantly downregulated anti-inflammatory and anti-oxidative protein expression nuclear Nrf2 and its target gene products including HO-1, catalase, GCLC, and NQO1 in the Keap1/Nrf2 signaling pathway than chrysophanol and emodin. This study first demonstrated that SKI and its major components protected against renal fibrosis by inhibiting oxidative stress and inflammation via simultaneous targeting IƙB/NF-ƙB and Keap1/Nrf2 signaling pathways, which illuminated the potential molecular mechanism of anti-oxidative and anti-inflammatory effects of SKI.

Omega-3 polyunsaturated fatty acids alleviate adenine-induced chronic renal failure via regulating ROS production and TGF-β/SMAD pathway.

The article "Omega-3 polyunsaturated fatty acids alleviate adenine-induced chronic renal failure via regulating ROS production and TGF-β/SMAD pathway", by J. Xu, Z.-P. Feng, H.-Y. Peng, P. Fu, published in Eur Rev Med Pharmacol Sci 2018; 22 (15): 5024-5032-DOI: 10.26355/eurrev_201808_15645-PMID: 30070341, has been retracted by the authors due to input errors which occurred in the experimental data. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/15645.

Protective effects of lycopene against adenine-induced chronic renal failure in rats

Objectives: Chronic renal failure (CRF) is a public health concern in both developed and developing countries. Therefore, there is still a need to look for secure and successful agents that can either minimise or prevent CRF from advancing to end-stage renal disorder. This study aimed to assess the effect of lycopene on adenine-induced CRF in the rat. Materials and Methods: Animals were divided into five groups (n = 6). Normal control group received normal vehicle, disease control group received orally adenine (50 mg/kg/day), L 100 group received orally lycopene (100 mg/kg/day) + adenine (50 mg/kg/day), L 200 group received orally lycopene (200 mg/kg/day) + adenine (50 mg/kg/day) and L 400 group received orally lycopene (400 mg/kg/day) + adenine (50 mg/kg/day) for 30 days. Results: Compared to the control group, the disease control group had decreased bodyweight, food intake and also increased the relative kidney weight and urine output. Adenine-treated group also significantly increased the blood urea nitrogen, serum creatinine, phosphorus, alkaline phosphatase, uric acid, magnesium and reduced the calcium, urine creatinine and urine urea nitrogen. Besides, adenine also gave a positive test of serum C-reactive protein and proteinuria. Histopathologically, adenine caused significant inflammatory changes to renal tissues compared with the normal control group. When administered concomitantly with adenine, lycopene alleviated all the measured adenine-induced physiological, biochemical and histological changes. Conclusion: We concluded from this analysis that oral lycopene administration could potentially mitigate the adverse effect of CRF that might be due to their antioxidant and free radical scavenging properties.

Changes in renal excretion pathways in rats with adenine-induced chronic renal failure

Changes in renal excretion pathways in rats with adenine-induced chronic renal failure

The Dysregulation of Eicosanoids and Bile Acids Correlates with Impaired Kidney Function and Renal Fibrosis in Chronic Renal Failure

Chronic renal failure (CRF) is an irreversible deterioration of the renal functions that characterized by fluid electrolyte unbalance and metabolic-endocrine dysfunctions. Increasing evidence demonstrated that metabolic disturbances, especially dyslipidemia and profound changes in lipid and lipoprotein metabolism were involved in CRF. Identification of lipids associated with impaired kidney functions may play important roles in the understanding of biochemical mechanism and CRF treatment. Ultra-performance liquid chromatography coupled with high-definition mass spectrometry-based lipidomics was performed to identify important differential lipids in adenine-induced CRF rats and investigate the undergoing anti-fibrotic mechanism of Polyporus umbellatus (PPU) and ergone (ERG). Linear correlation analysis was performed between lipid species intensities and creatinine levels in serum. Adenine-induced rats exhibited declining kidney function and renal fibrosis. Compared with control rats, a panel of lipid species was identified in the serum of CRF rats. Our further study demonstrated that eight lipids, including leukotrienes and bile acids, presented a strong linear correlation with serum creatinine levels. In addition, receiver operating characteristics analysis showed that eight lipids exhibited excellent area under the curve for differentiating CRF from control rats, with high sensitivity and specificity. The aberrant changes of clinical biochemistry data and dysregulation of eight lipids could be significantly improved by the administration of PPU and ergone. In conclusion, CRF might be associated with the disturbance of leukotriene metabolism, bile acid metabolism and lysophospholipid metabolism. The levels of eicosanoids and bile acids could be used for indicating kidney function impairment in CRF. PPU could improve renal functions and either fully or partially reversed the levels of eicosanoids and bile acids.

A fluorescence biosensor for therapeutic drug monitoring of vancomycin using in vivo microdialysis

Clinical vancomycin (Van) treatment is administered over a prolonged period to achieve a sustained therapeutic effect. Accurate, rapid, and continuous Van detection is an unmet medical monitoring need that can provide data-based guidance for doctors to adjust the dosage and treatment plan in real-world settings. In this study, we created a Van-specific, fluorescent biosensor that was combined with a microdialysis sampling technique to develop a rapid, simple, accurate, and sensitive detection method, which was validated for Van in vivo. A Van-specific probe was created by separately conjugating each of the two peptide chains of a dimeric derivative of the Van binding peptide L-Lys-D-Ala-D-Ala to a fluorescent dansyl chloride group. Subject-specific pharmacokinetics of Van was recorded in normal rabbits and rabbits with adenine-induced chronic renal failure (CRF), which indicated the feasibility of therapeutic drug monitoring in vivo. The area under the concentration–time curve (AUC0–last) was 10,715 min μg mL−1 (95% CI = 8,892 to 12,538) in the normal rabbits, and 14,822 and 19,025 min μg mL−1 in two selected CRF rabbits. Furthermore, using pharmacokinetic dosing of Van in a rabbit study, we designed the dosage and drug administration interval to achieve a sustained therapeutic effect. The normal rabbits received three Van doses, 20, 5, and 5 mg kg−1, administered at 0, 500, and 900 min, respectively. The CRF rabbits received two Van doses, 20 and 5 mg kg−1, administered at 0 and 600 min, respectively. Thus, we established an effective method for the continuous monitoring of Van. This method facilitates the detection of Van in clinical treatment and provides the scientific basis for an effective approach to monitor blood drug levels during the clinical treatment of various diseases.

Antioxidation, anti-inflammation and anti-fibrosis effect of phosphorylated polysaccharides from Pleurotus djamor mycelia on adenine-induced chronic renal failure mice

The mycelia polysaccharides (MPS) from Pleurotus djamor were prepared and purified by anion exchange column chromatography, and the phosphate content of phosphorylated MPS (PMPS) was 15.22 ± 0.37%. FT-IR spectra, HPLC and 1H and 13C-NMR results showed the PMPS contained α-pyranose structure and the peak area percentage composition of galacturonic acid and glucose were 13.01% and 85.82%, respectively. Animal experiment investigated the antioxidant, anti-inflammation, anti-fibrosis effects of PMPS on kidney in adenine-induced chronic renal failure (CRF) mice. All results including serum biochemical indices, histopathological observation, qRT-PCR, western blotting, immunohistochemical staining manifested the kidney injury could be remitted by PMPS interventions. This experiment suggested that PMPS could remit CRF and other kidney injury related diseases as one kind of dietary supplements and functional foods without toxic side effects.

Nephroprotective effects of ethanolic root extract of Azima tetracantha lam in adenine-induced chronic kidney failure in Wistar rats.

OBJECTIVES: To evaluate the effects of ethanolic root Ethanolic extract of Azima tetracantha. Lam roots (EEATR) in adenine.induced chronic kidney failure in Wistar albino ratsTo assess the antioxidant activity of EEATR. MATERIALS AND METHODS:Thirty rats were selected and allocated to five groups with six animals in each group. Group 1 was given normal saline (control), Group 2 – adenine, 0.75% 40 mg/kg, Group 3 – adenine and 250 mg/kg of EEATR, Group 4 – adenine and 500 mg/kg EEATR, and Group 5 – EEATR 500 mg/kg. Saline, adenine, and EEATR were given orally once daily for 28 days. EEATR was given 60 min before adenine administration. Urine output, blood urea nitrogen (BUN), creatinine, albumin, and total proteins were estimated. The histopathological changes in the kidneys were examined, and antioxidant property of the extract was assessed in the renal tissue.RESULTS:Adenine treated rats had a reduction in urine output (‒45%), food intake (‒46%), body weight (‒28%), total proteins (‒66%) and albumin (‒59%) and an increase in creatinine (950%), BUN (73.6%), and kidney weight (43.75%). Histological examination of the kidneys showed capillary congestion, tubular damage, glomerular distortion, and many oxalate crystals. Rats co-administered with EEATR 250 and 500 mg/kg had marked improvement (P ≤ 0.0001%) in all the above parameters with a marked reduction in size and number of oxalate crystals in the kidney. In the anti-oxidant assays, EEATR exhibited significant antioxidant activity.CONCLUSION:EEATR was found to be an effective nephroprotective agent in adenine-induced chronic renal failure in Wistar albino rats.

Nephroprotective effect of coadministration of curcumin and sildenafil in adenine-induced chronic renal failure in rats

BackgroundChronic renal failure (CRF) is a major public health problem worldwide. The pathophysiological basis of the disease and its complication include inflammation and oxidative stress, which are similar in humans and animals. In this study, we seek to develop new therapeutic modalities for CRF.ObjectiveThis study aimed to investigate the nephroprotective effects of curcumin (CUR) and/or sildenafil in adenine (AD) model of CRF.Materials and methodsRats were divided into five groups as follows: control naive group, AD group received AD 200 mg/kg/day orally to induce CRF, CUR group received CUR 200 mg/kg/day in addition to AD, sildenafil group received sildenafil 0.5 mg/kg/day in addition to AD, and combination group received combination of CUR 200 mg/kg/day and sildenafil 0.5 mg/kg/day in addition to AD. After consecutive 28 days of treatment, body weight, kidney index, and Doppler on renal artery assessments were done for all groups. In addition, kidney function tests and markers of oxidative stress were evaluated. Histopathological assessment of renal tissues and immunohistochemical staining for tumor necrosis factor-α were performed.ResultsCUR, sildenafil, and their combination significantly decreased body weight loss and urine volume and improved renal hemodynamic changes caused by AD. In addition, they significantly improved kidney function tests and biomarkers of oxidative stress. A significant down-regulation of tumor necrosis factor-α immunohistochemical expression was noted. They also brought histopathological changes induced by AD toward normal.ConclusionCUR and sildenafil may play a role in renal protection in AD-induced nephrotoxicity. The combined treatment showed better nephroprotective effect than either treatment alone did.

Rehmannia glutinosa polysaccharide increases the expression of erythropoietin and vascular endothelial growth factor in rats with chronic renal failure by activating hypoxia-inducible factor-2α

Background: To investigate the effect of Rehmannia glutinosa polysaccharide (RGP) in rats with chronic renal failure. Materials and Methods: In this study, we established a rat model of adenine-induced chronic renal failure. Hemoglobin (Hb), red blood cells (RBCs), total protein (TP), serum albumin (ALB), blood urea nitrogen (BUN), cystatin C (Cys C), and serum creatinine anhydride (SCA) were detected in the blood samples of rats. Hematoxylin and eosin staining was used to observe the pathological changes. Immunohistochemical was used to detect the protein expression of hypoxia-inducible factor (HIF)-2α, erythropoietin (EPO), and vascular endothelial growth factor (VEGF) and calculate the value of microvessel density (MVD) in renal tissues. M1001 and GPRRP + PT2385 groups were added to further validate the mechanism of RGP. Results: In the case of rats with chronic renal failure, GPRRP and EPO contributed to the repairment of renal tissue. The level of Hb, TP, and ALB, as well as RBC counts was significantly increased, and the renal function indexes, including BUN, SCA, and Cys C, were significantly decreased, and HIF-2α, EPO, VEGF, and MVD were significantly increased. The effects observed in M1001 group was similar to those in GPRRP group, but compared with GPRRP + PT2385 group, the biochemical indicators and renal function indexes were significantly decreased, which means HIF-2α inhibitor antagonized the protective effect of RGP. Conclusion: RGP played an essential role in repairing the renal injury in rats with chronic renal failure. The therapeutic mechanism of action may be related to the activation of HIF-2α, thereby increasing the expression of EPO and VEGF and then reducing renal anemia and renal tissue damage.

P0869EXOGENOUS OSTEOGENIC FACTOR 1 ADMINISTRATION ATTENUATED VASCULAR CALCIFICATION AND IMPROVED BONE DISORDERS IN CHRONIC UREMIC RATS

Abstract Background and Aims Hyperphosphatemia and secondary hyperparathyroidism are frequent complications in chronic kidney disease (CKD) which both contribute to increased morbidity and mortality in CKD. Osteogenic factor-1 (OP-1) is an important member of BMPs subfamily and its effects on CKD-associated mineral and bone disorders (MBD) is controversial. The study examined whether exogenous OP-1 administration can modulate disturbed CKD-MBD in adenine-induced chronic uremic rats Method Chronic renal failure was induced in adult male SD rats by feeding adenine-containing diet. After adenine diet feeding 3 weeks, animals were injected with OP-1 (5μg/kg/day) intraperitoneally for 2 weeks. The serum and urine phosphorus levels and associated mineral parameters, including fibroblast growth factor 23(FGF-23), DKK-1 and sclerostin were measured. Vascular calcification was assessed by immunohistochemistry staining on aortic tissue. Bony structure was evaluated by microCT (Bruker-microCT, Kontich, Belgium). Results A significant decrease of body weight and deteriorated renal function was observed in adenine and OP-1 treatment groups during study period and serum creatinine levels were similar (5.23 ±1.1 mg/dL vs. 5.4 ±1.2 mg/dL, p&amp;gt;0.05). Animals in OP-1 group had lower serum phosphorous (18.7±5.1 vs. 29.0±9.6 mg/dL, p&amp;lt;0.05) and intact parathyroid hormone levels (2906.1±1206.9 vs. 4669.7±2505.9 pg/dL, p&amp;lt;0.05) compared to adenine group. Decreased urine phosphorous excretion was noted in both groups without significant difference. Levels of serum FGF-23, sclerostin and DKK-1 were significantly lower in OP-1 treatment group (all p&amp;lt; 0.05). OP-1 administration diminished the staining of RUNX2 (59.1±3% of adenine-treated group), alkaline-phosphatase (49.4±5.7%), β-caterin (39.3±1.8%), BMP2 (43.2%±6.7%), and BMP7 (51.9±10%, all p &amp;lt;0.05). MicroCT revealed that bone mineral density was increased by OP-1 treatment (0.46±0.1 vs.0.39±0.06 g/cm3). Total volume was increased but bone volume was not changed. OP-1 administration did not affect trabecular thickness and trabecular number. Conclusion Our data indicated administration of exogenous OP-1 improved hyperparathyroidism and attenuated vascular calcification. OP-1 treatment was also associated with beneficial effects on bony structure in animals with renal failure.