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 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.

Transient nitric oxide reduction induces permanent cardiac systolic dysfunction and worsens kidney damage in rats with chronic kidney disease

2010 ◽  
Vol 298 (3) ◽  
pp. R815-R823 ◽  
Author(s):  
L. G. Bongartz ◽  
B. Braam ◽  
M. C. Verhaar ◽  
M. J. Cramer ◽  
R. Goldschmeding ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Left Ventricular Systolic Dysfunction ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Whole Body ◽  
Control Group ◽  
High Dose ◽  
No Production

Left ventricular systolic dysfunction (LVSD) in patients with chronic kidney disease (CKD) is associated with poorer prognosis. Because patients with CKD often exhibit progressively decreased nitric oxide (NO) availability and inhibition of NO production can reduce cardiac output, we hypothesized that loss of NO availability in CKD contributes to pathogenesis of LVSD. Subtotally nephrectomized (SNX) rats were treated with a low dose of the NO synthase inhibitor Nω-nitro-l-arginine (l-NNA; 20 mg/l water; SNX+l-NNA) and compared with relevant control groups. To study permanent changes separate from hemodynamic effects, l-NNA was stopped after week 8 and rats were followed up to week 15, until blood pressure was similar in SNX+l-NNA and SNX groups. To study effects of NO depletion alone, a control group with high-dose l-NNA (l-NNA-High: 100 mg/l) was included. Mild systolic dysfunction developed at week 13 after SNX. In SNX+l-NNA, systolic function decreased by almost 50% already from week 4 onward, together with markedly reduced whole body NO production and high mortality. In l-NNA-High, LVSD was not as severe as in SNX+l-NNA, and renal function was not affected. Both LVSD and NO depletion were reversible in l-NNA-High after l-NNA was stopped, but both were persistently low in SNX+l-NNA. Proteinuria increased compared with rats with SNX, and glomerulosclerosis and cardiac fibrosis were worsened. We conclude that SNX+l-NNA induced accelerated and permanent LVSD that was functionally and structurally different from CKD or NO depletion alone. Availability of NO appears to play a pivotal role in maintaining cardiac function in CKD.

Nitric oxide deficiency in chronic kidney disease

2008 ◽  
Vol 294 (1) ◽  
pp. F1-F9 ◽  
Author(s):  
Chris Baylis
Keyword(s):  
Nitric Oxide ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Metabolic Pathways ◽  
Cardiovascular Complications ◽  
No Production ◽  
Nos Inhibitors ◽  
Rate Of Progression ◽  
Nitric Oxide Deficiency ◽  
Circulating Levels

The overall production of nitric oxide (NO) is decreased in chronic kidney disease (CKD) which contributes to cardiovascular events and further progression of kidney damage. There are many likely causes of NO deficiency in CKD and the areas surveyed in this review are: 1. Limitations on substrate (l-Arginine) availability, probably due to impaired renal l-Arginine biosynthesis, decreased transport of l-Arginine into endothelial cells and possible competition between NOS and competing metabolic pathways, such as arginase. 2. Increased circulating levels of endogenous NO synthase (NOS) inhibitors, in particular asymmetric dimethylarginine (ADMA). Increased methylation of proteins and their subsequent breakdown to release free ADMA may contribute but the major culprit is probably reduced ADMA catabolism by the enzymes dimethylarginine dimethylaminohydrolases. 3. Reduced renal cortex abundance of the neuronal NOS (nNOS)α protein correlates with injury while increasing nNOSβ abundance may provide a compensatory, protective response. Interventions that can restore NO production by targeting these various pathways are likely to reduce the cardiovascular complications of CKD as well as slowing the rate of progression.

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 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.

Maturational changes in the regulation of pulmonary vascular tone by nitric oxide in neonatal rats

2007 ◽  
Vol 293 (5) ◽  
pp. L1261-L1270 ◽  
Author(s):  
Louis G. Chicoine ◽  
Michael L. Paffett ◽  
Mark R. Girton ◽  
Matthew J. Metropoulus ◽  
Mandar S. Joshi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Guanylyl Cyclase ◽  
Vascular Tone ◽  
Age Groups ◽  
Soluble Guanylyl Cyclase ◽  
No Production ◽  
Sprague Dawley ◽  
No Donor ◽  
Early Postnatal Development ◽  
Old Rats

Nitric oxide (NO) is an important regulator of vasomotor tone in the pulmonary circulation. We tested the hypothesis that the role NO plays in regulating vascular tone changes during early postnatal development. Isolated, perfused lungs from 7- and 14-day-old Sprague-Dawley rats were studied. Baseline total pulmonary vascular resistance (PVR) was not different between age groups. The addition of KCl to the perfusate caused a concentration-dependent increase in PVR that did not differ between age groups. However, the nitric oxide synthase (NOS) inhibitor Nω-nitro-l-arginine augmented the K+-induced increase in PVR in both groups, and the effect was greater in lungs from 14-day-old rats vs. 7-day-old rats. Lung levels of total endothelial, inducible, and neuronal NOS proteins were not different between groups; however, the production rate of exhaled NO was greater in lungs from 14-day-old rats compared with those of 7-day-old rats. Vasodilation to 0.1 μM of the NO donor spermine NONOate was greater in 14-day lungs than in 7-day lungs, and lung levels of both soluble guanylyl cyclase and cGMP were greater at 14 days than at 7 days. Vasodilation to 100 μM of the cGMP analog 8-(4-chlorophenylthio)guanosine-3′,5′-cyclic monophosphate was greater in 7-day lungs than in 14-day lungs. Our results demonstrate that the pulmonary vascular bed depends more on NO production to modulate vascular tone at 14 days than at 7 days of age. The observed differences in NO sensitivity may be due to maturational increases in soluble guanylyl cyclase protein levels.

Abstract P242: The Role Of Kappa Opioid Receptors In The Development Of Hypertension And Kidney Injury In Sprague-Dawley Rats

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Daria Golosova ◽  
Adrian Zietara ◽  
Ruslan Bohovyk ◽  
Vladislav Levchenko ◽  
Alexander Staruschenko
Keyword(s):  
Blood Pressure ◽  
Sprague Dawley ◽  
Glomerular Injury ◽  
Kappa Opioid ◽  
Injury Score ◽  
Calcium Response ◽  
Blood Pressure Elevation ◽  
Isolated Glomeruli ◽  
Pressure Elevation ◽  
Sd Rats

The extensive use of opioid-based pain management strongly correlates with poor cardiovascular and cardiorenal outcomes. Our recent studies suggest that treatment with kappa opioid receptor (KOR) agonist BRL 52537 leads to the progression of chronic kidney disease (CKD) and aggravation of salt-sensitive hypertension. We hypothesize that stimulation of KORs leads to blood pressure elevation, albuminuria, and kidney damage in healthy Sprague-Dawley (SD) rats. To characterize the effect of the KOR agonist BRL 52537 on the development of blood pressure and kidney function in vivo , SD rats were treated with a daily i.v. bolus infusion of BRL 52537 or a corresponding vehicle. To test the contribution of KOR stimulation on calcium homeostasis in podocytes, BRL 52537 was used on freshly isolated glomeruli from SD rats. Single-channel analysis was applied to assess the effect of KORs stimulation on TRPC6 channel activity in the human immortalized podocytes. Chronic treatment with BRL 52537 leads to increased mean arterial pressure (88±1 vs 101±4 mmHg, vehicle vs treated, p<0.05), podocyte basal calcium (90±12 vs 216±16 a.u., vehicle vs treated, p<0.05), and GFB impairment in SD rats which is reflected by a transient increase in albumin excretion (Alb/cre ratio 0.35±0.1 vs 0.72±0.2, vehicle vs treated, p<0.05). Cumulative probability distribution analysis of the glomerular injury score revealed a rightward shift toward a high glomerular injury score in the group treated with BRL 52537 (p<0.05). Angiotensin II level was higher in a BRL-treated group (156±17 vs 232±59 pmol, vehicle vs treated, p=0.065); however, it did not reach a statistical difference. Acute application of BRL 52537 resulted in sustained calcium response (0.23±0.01 a.u., Fluo4/FuraRed, maximum calcium response) in freshly isolated glomeruli from SD rats. Furthermore, patch-clamp experiments in human immortalized podocytes (cell-attached configuration) revealed that BRL 52537 activated TRPC6 channels. Taken together, these data support the hypothesis that administration of opioids in SD rats leads to activation of the KOR/TRPC6 pathway, which in turn led to glomerular filtration barrier impairment, increased glomerular damage, and blood pressure elevation.

Abstract 109: Gamma-adducin Effects on Microvascular Function- a Common Link of Hypertension Induced Chronic Kidney Disease and Cognitive Impairments

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Fan Fan ◽  
Shaoxun Wang ◽  
Paige N Mims ◽  
Chao Zhang ◽  
Richard J Roman
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Genetic Model ◽  
Cognitive Impairments ◽  
Microvascular Dysfunction ◽  
Small Region ◽  
Glomerular Injury ◽  
Flow Pressure ◽  
Underlying Mechanisms ◽  
Stop Flow

Chronic kidney disease (CKD) and cognitive impairments are common complications of hypertension. Increasing evidence suggests that the cognitive impairments associated with CKD may be related to microvascular dysfunction, however, the underlying mechanisms remain to be elucidated. FHH is a genetic model of hypertension-induced nephropathy. We found that the myogenic response and autoregulation of the renal and cerebral circulation is impaired in FHH rats, and was restored in a FHH.1 BN congenic strain in which a small region of Chr. 1 containing 15 genes, including Add3, from BN rats was transferred into the FHH background. The present study examined whether Add3 contributes to hypertension related CKD, and is associated with the development of cognitive impairments due to microvascular dysfunction. FHH rats exhibited impaired autoregulation of RBF in comparison with FHH.1 BN rats. Pgc estimated from the stop flow pressure increased by 20 mmHg in FHH rats when RPP was increased from 100 to 140 mmHg versus only 4 mmHg in FHH.1 BN . FHH rats developed severe renal injury, and proteinuria rose from 37 ± 2 to 260 ± 32 mg/day as they aged from 12 to 21 weeks, but rose by a significant lesser extent in FHH.1 BN and FHH.Add3 rats. Glomerular injury scores were 3.31 ± 0.01, 2.54 ± 0.01 and 2.50 ± 0.03, and areas of fibrosis in renal cortex were 23.57 ± 1.04%, 8.28 ± 0.33 and 4.71 ± 0.3 in DOCA/salt induced hypertensive FHH, FHH.1 BN and FHH.Add3 rats, respectively. CBF rose by 99 ± 7%, 64 ± 5% and 42 ± 4% in FHH, FHH.1 BN and FHH.Add3 rats, respectively, when MAP was increased from 100 to 190 mmHg, demonstrating impaired autoregulation of CBF in FHH rats was partially rescued with the replacement of wildtype Add3. BBB leakage was greater in FHH rats than in FHH.1 BN and FHH.Add3 rats, and hypertensive FHH rats exhibited marked neurodegeneration and vascular remodeling of the neocortex and hippocampus. The hypertensive FHH rats took 2.5 times longer time to escape from an eight-arm water maze in comparison to FHH.1 BN rats suggesting cognitive deficit. These results indicate that Add3 may play a role in the development of hypertension related CKD and cognitive impairments in FHH rats associated with microvascular dysfunction.

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