scholarly journals Pharmacokinetics and Pharmacodynamics of the Combination of Rhein and Curcumin in the Treatment of Chronic Kidney Disease in Rats

2020 ◽  
Vol 11 ◽  
Author(s):  
Xiaoying He ◽  
Guowei Li ◽  
Yuanyuan Chen ◽  
Qiming Xiao ◽  
Xinwei Yu ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Molecular Docking ◽  
Kidney Disease ◽  
Interaction Mechanism ◽  
Ultra Performance Liquid Chromatography ◽  
Renal Tissue ◽  
Combination Group ◽  
Sprague Dawley ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Sd Rats

Objectives: The interaction between the components of traditional Chinese medicine (TCM) is an important basis for their synergy. Rhein and curcumin exert various pharmacological activities, including anti-tumour, anti-inflammatory, antioxidant, anti-fibrosis and renoprotective effects. However, no investigation has reported the synergistic anti-fibrosis effect yet. This study aims at determine the pharmacokinetics and pharmacodynamics of the combination of rhein and curcumin in the treatment for chronic kidney disease in rats.Design: Fifty two male Sprague-Dawley (SD) rats were randomly divided into rhein group, curcumin group and their combination group for pharmacodynamics studies. HE and Masson staining was conducted to observe the changes of renal morphology. Kits were used to detect the level of urea nitrogen (BUN) and creatinine (Scr). For pharmacokinetic study, 36 SD rats were randomly divided into rhein group, curcumin group and a combination group, the content of rhein and curcumin in plasma and renal tissue was determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). In additon, molecular docking method and cell experiments was used to disclose the interaction mechanism between curcumin and rhein.Results: The pharmacodynamic results showed that the degree of renal fibrosis was improved obviously by co-administration rhein and curcumin. Meanwhile, compared to single administration, the Cmax and AUC of rhein and curcumin in plasma and renal tissue were enhanced significantly after co-administration. Moreover, the result of molecular docking and cell experiments showed that both two compounds could interact with P-gp, CYP2C9 and CYP2C19.Conclusion: Together, these findings demonstrated that rhein and curcumin had a synergistic effect in ameliorateing chonic kidney disease, providing an important explanation on the synergistic mechanism of curcumin and rhein from a pharmacokinetic viewpoint.

scholarly journals Altered Emotional Phenotypes in Chronic Kidney Disease Following 5/6 Nephrectomy

2021 ◽  
Vol 11 (7) ◽  
pp. 882
Author(s):  
Yeon Hee Yu ◽  
Seong-Wook Kim ◽  
Dae-Kyoon Park ◽  
Ho-Yeon Song ◽  
Duk-Soo Kim ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Local Field ◽  
Smooth Muscle Actin ◽  
Local Field Potentials ◽  
Renal Tissue ◽  
Field Potentials ◽  
Wild Type ◽  
Sprague Dawley ◽  
Rat Models

Increased prevalence of chronic kidney disease (CKD) and neurological disorders including cerebrovascular disease, cognitive impairment, peripheral neuropathy, and dysfunction of central nervous system have been reported during the natural history of CKD. Psychological distress and depression are serious concerns in patients with CKD. However, the relevance of CKD due to decline in renal function and the pathophysiology of emotional deterioration is not clear. Male Sprague Dawley rats were divided into three groups: sham control, 5/6 nephrectomy at 4 weeks, and 5/6 nephrectomy at 10 weeks. Behavior tests, local field potentials, and histology and laboratory tests were conducted and investigated. We provided direct evidence showing that CKD rat models exhibited anxiogenic behaviors and depression-like phenotypes, along with altered hippocampal neural oscillations at 1–12 Hz. We generated CKD rat models by performing 5/6 nephrectomy, and identified higher level of serum creatinine and blood urea nitrogen (BUN) in CKD rats than in wild-type, depending on time. In addition, the level of α-smooth muscle actin (α-SMA) and collagen I for renal tissue was markedly elevated, with worsening fibrosis due to renal failures. The level of anxiety and depression-like behaviors increased in the 10-week CKD rat models compared with the 4-week rat models. In the recording of local field potentials, the power of delta (1–4 Hz), theta (4–7 Hz), and alpha rhythm (7–12 Hz) was significantly increased in the hippocampus of CKD rats compared with wild-type rats. Together, our findings indicated that anxiogenic behaviors and depression can be induced by CKD, and these abnormal symptoms can be worsened as the onset of CKD was prolonged. In conclusion, our results show that the hippocampus is vulnerable to uremia.

scholarly journals DOCA/NaCl-induced chronic kidney disease: a comparison of renal nitric oxide production in resistant and susceptible rat strains

2007 ◽  
Vol 292 (1) ◽  
pp. F192-F196 ◽  
Author(s):  
Aaron Erdely ◽  
Gary Freshour ◽  
You-Lin Tain ◽  
Kevin Engels ◽  
Chris Baylis
Keyword(s):  
Nitric Oxide ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Creatinine Clearance ◽  
No Production ◽  
Sprague Dawley ◽  
Glomerular Injury ◽  
Protein Excretion ◽  
Sd Rats ◽  
Mild Reduction

Recent studies show nitric oxide (NO) deficiency is both a cause and consequence of chronic kidney disease (CKD). Reduced renal neuronal NO synthase (nNOS) abundance and activity parallel development of CKD with different models in the Sprague-Dawley (SD) rats, whereas Wistar Furth (WF) rats are protected against CKD and show preserved renal NO production. In this study, we compared renal NO in response to DOCA/salt-induced injury between the WF and SD. Studies were conducted on sham WF ( n = 6) and SD ( n = 6) and uninephrectized (UNX)+75 mg DOCA+1% NaCl (WF n = 9; SD n = 10) rats followed for 5 wk. Kidneys were harvested for Western blot, NOS activity, and histology. Other measurements included creatinine clearance and 24-h total NO production and urinary protein excretion. Absolute values of kidney weight were lower in WF than SD rats that showed similar percent increases with UNX+DOCA/NaCl. Proteinuria and decreased creatinine clearance were present in the SD but not the WF rats following UNX+DOCA/NaCl. Glomerular injury was mild in the WF compared with SD rats that showed many globally damaged glomeruli. Although renal nNOS abundance was decreased in both strains (higher baseline in WF), soluble NOS activity was maintained in the WF but significantly reduced in the SD rats. Renal endothelial NOS abundance and membrane NOS activity were unaffected by treatment. In summary, WF rats showed resistance to UNX+DOCA/NaCl-induced CKD with maintained renal NO production despite mild reduction in nNOS abundance. Further studies are needed to evaluate how WF rats maintain renal NO production despite similar changes in abundance as the vulnerable SD strain.

scholarly journals Renal oxygenation during the early stages of adenine-induced chronic kidney disease

2019 ◽  
Vol 317 (5) ◽  
pp. F1189-F1200 ◽  
Author(s):  
Md Mahbub Ullah ◽  
Connie P. C. Ow ◽  
Lucinda M. Hilliard Krause ◽  
Roger G. Evans
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Dysfunction ◽  
Hypoxia Inducible Factor ◽  
Early Event ◽  
Pathological Feature ◽  
Sprague Dawley ◽  
Creatinine Concentration ◽  
Medullary Tissue ◽  
Clark Electrode

To assess whether renal hypoxia is an early event in adenine-induced chronic kidney disease, adenine (100 mg) or its vehicle was administered to male Sprague-Dawley rats by daily oral gavage for 7 days. Kidney oxygenation was assessed by 1) blood oximetry and Clark electrode in thiobutabarbital-anesthetized rats, 2) radiotelemetry in unanesthetized rats, and 3) expression of hypoxia-inducible factor (HIF)-1α and HIF-2α protein. After 7 days of treatment, under anesthesia, renal O2 delivery was 51% less, whereas renal O2 consumption was 65% less, in adenine-treated rats than in vehicle-treated rats. Tissue Po2 measured by Clark electrode was similar in the renal cortex but 44% less in the medulla of adenine-treated rats than in that of vehicle-treated rats. In contrast, in unanesthetized rats, both cortical and medullary tissue Po2 measured by radiotelemetry remained stable across 7 days of adenine treatment. Notably, anesthesia and laparotomy led to greater reductions in medullary tissue Po2 measured by radiotelemetry in rats treated with adenine (37%) than in vehicle-treated rats (16%), possibly explaining differences between our observations with Clark electrodes and radiotelemetry. Renal expression of HIF-1α was less after 7 days of adenine treatment than after vehicle treatment, whereas expression of HIF-2α did not differ significantly between the two groups. Renal dysfunction was evident after 7 days of adenine treatment, with glomerular filtration rate 65% less and serum creatinine concentration 183% greater in adenine-treated rats than in vehicle-treated rats. Renal cortical tissue hypoxia may not precede renal dysfunction in adenine-induced chronic kidney disease and so may not be an early pathological feature in this model.

scholarly journals Intermittent hypoxia exacerbates increased blood pressure in rats with chronic kidney disease

2018 ◽  
Vol 315 (4) ◽  
pp. F927-F941 ◽  
Author(s):  
Jennifer L. Riggs ◽  
Carolyn E. Pace ◽  
Heather H. Ward ◽  
Laura V. Gonzalez Bosc ◽  
Lynnette Rios ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Intermittent Hypoxia ◽  
Interstitial Fibrosis ◽  
Control Diet ◽  
Kidney Injury ◽  
Kidney Damage ◽  
Plasma Creatinine ◽  
Sprague Dawley

Kidney injury and sleep apnea (SA) are independent risk factors for hypertension. Exposing rats to intermittent hypoxia (IH) to simulate SA increases blood pressure whereas adenine feeding causes persistent kidney damage to model chronic kidney disease (CKD). We hypothesized that exposing CKD rats to IH would exacerbate the development of hypertension and renal failure. Male Sprague-Dawley rats were fed a 0.2% adenine diet or control diet (Control) until blood urea nitrogen was >120 mg/dl in adenine-fed rats (14 ± 4 days, mean ± SE). After 2 wk of recovery on normal chow, rats were exposed to IH (20 exposures/h of 5% O2-5% CO2 7 h/day) or control conditions (Air) for 6 wk. Mean arterial pressure (MAP) was monitored with telemeters, and plasma and urine samples were collected weekly to calculate creatinine clearance as an index of glomerular filtration rate (GFR). Prior to IH, adenine-fed rats had higher blood pressure than rats on control diet. IH treatment increased MAP in both groups, and after 6 wk, MAP levels in the CKD/IH rats were greater than those in the CKD/Air and Control/IH rats. MAP levels in the Control/Air rats were lower than those in the other three groups. Kidney histology revealed crystalline deposits, tubule dilation, and interstitial fibrosis in both CKD groups. IH caused no additional kidney damage. Plasma creatinine was similarly increased in both CKD groups throughout whereas IH alone increased plasma creatinine. IH increases blood pressure further in CKD rats without augmenting declines in GFR but appears to impair GFR in healthy rats. We speculate that treating SA might decrease hypertension development in CKD patients and protect renal function in SA patients.

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 Association between MR-proADM concentration and treatment intensity of antihypertensive agents in chronic kidney disease patients with insufficient blood pressure control

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Motoshi Iwao ◽  
Ryota Tanaka ◽  
Yosuke Suzuki ◽  
Takeshi Nakata ◽  
Kohei Aoki ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Antihypertensive Drugs ◽  
Antihypertensive Agents ◽  
Pressure Control ◽  
Ultra Performance Liquid Chromatography ◽  
Treatment Intensity ◽  
Cross Sectional ◽  
Intensity Score

AbstractResponse to antihypertensive drugs in patients with chronic kidney disease (CKD) has great interindividual variability. Adrenomedullin (ADM) is produced abundantly in hypertension, but clearance is very rapid. Mid-regional proADM (MR-proADM) produced from an ADM precursor is considered a surrogate biomarker for quantification of ADM. We investigated the association of MR-proADM with antihypertensive resistance in CKD patients with poor blood pressure (BP) control. This cross-sectional study analyzed 33 CKD patients with poor BP control defined as failure to achieve target BP despite at least two classes of antihypertensive drugs. Treatment intensity score was calculated to facilitate comparability of antihypertensive regimens across subjects taking different drugs. Plasma MR-proADM concentration was measured using ultra-performance liquid chromatography coupled with tandem mass spectrometry. Plasma MR-proADM concentration correlated with estimated glomerular filtration rate (eGFR) (r =  − 0.777, p < 0.001). Treatment intensity score correlated positively with plasma MR-proADM concentration (r = 0.355, p = 0.043), and the correlation was further enhanced after correction by weight (r = 0.538, p = 0.001). Single and multiple regression analysis identified MR-proADM concentration (p = 0.005) as independently associated with weight-corrected treatment intensity score. MR-proADM may be useful as a biomarker to determine the therapeutic intensity of antihypertensive drugs in CKD patients with poor BP control.

scholarly journals Chronic exposure to hypoxia attenuates renal injury and innate immunity activation in the remnant kidney model

2019 ◽  
Vol 317 (5) ◽  
pp. F1285-F1292 ◽  
Author(s):  
Lisienny Campoli Tono Rempel ◽  
Viviane Dias Faustino ◽  
Orestes Foresto-Neto ◽  
Camilla Fanelli ◽  
Simone Costa Alarcon Arias ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Innate Immunity ◽  
Kidney Disease ◽  
Renal Injury ◽  
Cortical Area ◽  
Prolonged Exposure ◽  
Capillary Density ◽  
Renal Tissue ◽  
Peritubular Capillary

Hypoxia is thought to influence the pathogenesis of chronic kidney disease, but direct evidence that prolonged exposure to tissue hypoxia initiates or aggravates chronic kidney disease is lacking. We tested this hypothesis by chronically exposing normal rats and rats with 5/6 nephrectomy (Nx) to hypoxia. In addition, we investigated whether such effect of hypoxia would involve activation of innate immunity. Adult male Munich-Wistar rats underwent Nx ( n = 54) or sham surgery (sham; n = 52). Twenty-six sham rats and 26 Nx rats remained in normoxia, whereas 26 sham rats and 28 Nx rats were kept in a normobaric hypoxia chamber (12% O2) for 8 wk. Hypoxia was confirmed by immunohistochemistry for pimonidazole. Hypoxia was confined to the medullary area in sham + normoxia rats and spread to the cortical area in sham + hypoxia rats, without changing the peritubular capillary density. Exposure to hypoxia promoted no renal injury or elevation of the content of IL-1β or Toll-like receptor 4 in sham rats. In Nx, hypoxia also extended to the cortical area without ameliorating the peritubular capillary rarefaction but, unexpectedly, attenuated hypertension, inflammation, innate immunity activation, renal injury, and oxidative stress. The present study, in disagreement with current concepts, shows evidence that hypoxia exerts a renoprotective effect in the Nx model instead of acting as a factor of renal injury. The mechanisms for this unexpected beneficial effect are unclear and may involve NF-κB inhibition, amelioration of oxidative stress, and limitation of angiotensin II production by the renal tissue.

scholarly journals Pharmacokinetics and pharmacodynamics of TTI-101, a STAT3 inhibitor that blocks muscle proteolysis in rats with chronic kidney disease

2020 ◽  
Vol 319 (1) ◽  
pp. F84-F92 ◽  
Author(s):  
Liping Zhang ◽  
Ying Wang ◽  
Yanlan Dong ◽  
Zihong Chen ◽  
Thomas K. Eckols ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Plasma Levels ◽  
Muscle Protein ◽  
Plasma Concentrations ◽  
Maximum Plasma ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Molecule Inhibitor ◽  
Enhancer Binding Protein ◽  
Maximal Plasma

Loss of muscle proteins increases the morbidity and mortality of patients with chronic kidney disease (CKD), and there are no reliable preventive treatments. We uncovered a STAT3/CCAAT-enhancer-binding protein-δ to myostatin signaling pathway that activates muscle protein degradation in mice with CKD or cancer; we also identified a small-molecule inhibitor of STAT3 (TTI-101) that blocks this pathway. To evaluate TTI-101 as a treatment for CKD-induced cachexia, we measured TTI-101 pharmacokinetics and pharmacodynamics in control and CKD rats that were orally administered TTI-101or its diluent. The following two groups of gavage-fed rats were studied: sham-operated control rats and CKD rats. Plasma was collected serially (0, 0.25, 0.5, 1, 2, 4, 8, and 24 h) following TTI-101 administration (at oral doses of 0, 10, 30, or 100 mg/kg). Plasma levels of TTI-101 were measured by LC-MS/MS, and pharmacokinetic results were analyzed with the PKSolver program. Plasma TTI-101 levels increased linearly with doses; the maximum plasma concentrations and time to maximal plasma levels (~1 h) were similar in sham-operated control rats and CKD rats. Notably, gavage treatment of TTI-101 for 3 days produced TTI-101 muscle levels in sham control rats and CKD rats that were not significantly different. CKD rats that received TTI-101 for 7 days had suppression of activated STAT3 and improved muscle grip strength; there also was a trend for increasing body and muscle weights. TTI-101 was tolerated at doses of 100 mg·kg−1·day−1 for 7 days. These results with TTI-101 in rats warrant its development as a treatment for cachexia in humans.

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