Kidney Disease In Rats Research Articles

18F]FPYKYNE- Losartan AT1 Receptor Binding Is Reduced in Chronic Kidney Disease Rat Model With Pet Imaging

Significant renal mass reduction induced by 5/6 subtotal nephrectomy is associated with a chain of events that culminates in hypertension and chronic kidney disease (CKD). The leading cause of death in CKD is cardiovascular diseases. Angiotensin type 1 receptor (AT1R) is thought to play a role in progression of the disease and development of complications because of the beneficial effect of AT1R blockade. However, conflicting results were reported on intrarenal AT1R levels in CKD models. Noninvasive imaging will allow for identification of receptor expression abnormalities, understanding the contribution of the AT1R to the progression of disease and will aid to guide medication.

Abstract 497: The Influence of Long Term Voluntary Exercise on Cardiac Autonomic Function in Conscious Chronic Kidney Disease Animals

Background: Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular morbidity and mortality. Exercise has enduring cardio-protective effects that arise, in part, as a result of improved autonomic control of heart rate (HR). The aim of our study was to determine if voluntary exercise improves autonomic function in conscious animals with CKD, specifically examining the balance between sympathetic and parasympathetic cardiac tone. Methods: Mixed sex Lewis and Lewis polycystic kidney disease (LPK) rats were used. Animals were divided into four groups: sedentary Lewis (SL) (n=4); exercise Lewis (EL) (n=3); sedentary LPK (SLPK) (n=2); and exercise LPK (ELPK) (n=2). The exercise group was provided unlimited access to an activity wheel in their home cage from 5 weeks of age, and the sedentary group a locked activity wheel. At 10 weeks of age, rats were implanted with radio-telemetry probes. At 13 weeks, resting HR, mean blood pressure (MBP) and activity were determined over a 20 minute period during the day and changes in HR in response to atenolol (AT, 1 mg/kg i.p.) and methylatropine (MA, 2 mg/kg, i.p.). Results: Resting HR and activity was not significantly different between any groups. MBP was higher in both ELPK and SLPK compared with Lewis (average: 213.4 ± 3.8 vs. 96.8 ± 2.8 mmHg, P <0.05). In the ELPK compared to SLPK, atenolol produced a smaller reduction in HR (-47.5 ± 0.8 vs. -66.9 ± 2.8 bpm, P <0.05) and methylatropine a greater increase in HR (85.8 ± 5.3 vs. 54.9 ± 5.1 bpm, P <0.05) indicating a relative reduction in sympathetic and increase in vagal tone in the exercised animals. This was not observed in the Lewis rats. Conclusion: Our preliminary data demonstrates that exercise promotes vagal control of HR in rodents with CKD. Future studies will identify if this translates to an improvement in baroreflex control of HR.

Erythropoiesis-stimulating agent improves flow-mediated dilation via reduction of oxidative stress in chronic kidney disease rats

Purpose: Anemia in chronic kidney disease (CKD) patients is an important risk factor for cardiovascular disease, and treatment of anemia by erythropoiesis-stimulating agent (ESA) has been reported to improved QOL in CKD patients. Many cardiovascular diseases are initiated by endothelial dysfunction. In this study, the influence of ESA on endothelial function was evaluated by measuring flow-mediated dilation (FMD) in anesthetized 5/6 nephrectomized (Nx) rats. Methods: Nx was established in male SD rats (7 weeks old). Continuous erythropoietin receptor activator (C.E.R.A., epoetin beta pegol; 0.6 μg/kg, once every 2 weeks) was subcutaneously administered from 1 week after Nx. Nine weeks later, endothelial function was evaluated by measuring FMD in the femoral artery of anesthetized rats with a high-resolution ultrasound system. FMD was calculated from the change in diameter of the femoral artery following reperfusion after 5 min occlusion. After that, the femoral artery was harvested and used for western blot analysis. Plasma levels of 8-OHdG and hydroperoxide were determined by ELISA and free radical elective evaluator, respectively. Results: C.E.R.A. normalized hemoglobin level of Nx rats (Nx, 12.5±0.5; Nx+C.E.R.A., 14.7±0.6 g/dL; mean ± SE, n=9) at 9 weeks after Nx. No changes in blood pressure or renal function were observed with C.E.R.A. treatment. In anesthetized rats, reperfusion after 5 min of hindlimb ischemia induced an instantaneous increase in femoral blood flow (i.e. reactive hyperemia). Following hyperemia, dilation of the femoral artery (i.e. FMD) was observed, with a maximum increase in dilation relative to baseline diameter occurring 0.5–1 min after reperfusion. C.E.R.A. significantly increased FMD of Nx rats (Nx, 11.8±2.3; Nx+C.E.R.A., 22.4±4.4%; n=9). Endothelium-independent vasodilation induced by nitroglycerin injection was not influenced by C.E.R.A treatment. C.E.R.A. significantly enhanced phosphorylation of endothelial nitric oxide synthase (eNOS) in the femoral artery. Furthermore, Nox4 protein (a NADPH oxidase component) and nitrotyrosine (a marker of peroxynitrite) were significantly decreased in the femoral arteries of C.E.R.A.-treated rats. On the other hand, plasma 8-OHdG and hydroperoxide, which are other markers of oxidative stress, were not influenced by C.E.R.A. treatment. Conclusion: These results demonstrated that C.E.R.A. improved endothelial function in Nx rats, possibly through reduction of regional oxidative stress in the arteries. The endothelial protective effect of ESA might contribute to the improved prognosis in CKD patients treated with ESA.

Beraprost sodium improves survival rates in anti-glomerular basement membrane glomerulonephritis and 5/6 nephrectomized chronic kidney disease rats

Beraprost sodium, a stable prostacyclin analog, was showed to improve survival rates in two different rat models, anti-glomerular basement membrane (GBM) glomerulonephritis (GN) and 5/6 nephrectomized (Nx) chronic kidney disease (CKD) rats. In the anti-GBM rat, beraprost sodium (0.2 and 0.6mg/kg/day) improved survival rate (hazard ratio for beraprost sodium 0.6mg/kg/day group, 0.10; 95% confidence interval, 0.01 to 0.68). Subsequently, in the 5/6 Nx CKD rat, beraprost sodium (0.6mg/kg/day) improved survival rate (hazard ratio for beraprost sodium, 0.46; 95% confidence interval, 0.23 to 0.92), serum creatinine doubling time and the slope of the reciprocal of serum creatinine. In the anti-GBM GN rats, beraprost sodium suppressed the serum accumulation of representative uremic toxins such as indoxyl sulfate. Furthermore, beraprost sodium inhibited human aortic endothelial cell (HAEC) injury induced by indoxyl sulfate, indicating that beraprost sodium might have a protective effect against cardiovascular damage due to CKD. These results show that beraprost sodium can improve the survival rates in two rat models of anti-GBM GN and 5/6 Nx CKD rats by protecting endothelial cells and thereby ameliorating decreased renal function. Therefore, clinical studies are needed in patients with chronic kidney failure to determine whether beraprost sodium will become a useful medication in CKD.

Dietary iron restriction prevents further deterioration of renal damage in a chronic kidney disease rat model

Iron accumulation is associated with the pathogenesis of chronic kidney disease (CKD). However, little is known about the effects of isolated iron restriction against CKD. We have recently reported that iron restriction prevents the development of renal damage in the well established 5/6 nephrectomy rat model of CKD. Herein, we investigated the therapeutic effects of iron restriction on preexisting hypertension and renal damage in a rat model of CKD. CKD was induced by 5/6 nephrectomy in Sprague-Dawley rats. After surgery, 5/6 nephrectomized rats were given an iron-restricted diet from 1 day to 16 weeks for prevention protocol or from 8 to 16 weeks for rescue protocol. Other CKD rats were given a normal diet. At 16 weeks after surgery, CKD rats developed hypertension and renal damage. Early intervention with iron restriction prevented the development of hypertension and vascular remodeling. By contrast, late intervention with iron restriction did not remarkably ameliorate preexisting hypertension and vascular remodeling in CKD rats. On the contrary, late intervention with iron restriction prevented further progression of preexisting renal damage in CKD rats. Interestingly, iron restriction led to increased urinary sodium and decreased urinary potassium excretions in CKD rats. Moreover, iron restriction markedly attenuated renal expression of nuclear mineralocorticoid receptor and Rac1 activity in CKD rats. Iron restriction prevented further deterioration of preexisting renal damage. The beneficial effects of iron restriction on renal damage seem to be associated with inhibition of renal mineralocorticoid receptor signaling.

Chronic effects of dietary vitamin D deficiency without increased calcium supplementation on the progression of experimental polycystic kidney disease

Increasing evidence indicates that vitamin D deficiency exacerbates chronic kidney injury, but its effects on renal enlargement in polycystic kidney disease (PKD) are not known. In this study, male Lewis polycystic kidney disease (LPK) rats received a normal diet (ND; AIN-93G) supplemented with or without cholecalciferol (vitamin D-deficient diet, VDD; both 0.5% calcium), commenced at either postnatal week 3 (until weeks 10-20; study 1) or from week 10 (until week 20; study 2). Levels of 25-hydroxy vitamin D were reduced in groups receiving the VDD (12 ± 1 nmol/l vs. 116 ± 5 in ND; P < 0.001). In study 1, food intake and weight gain increased by ∼25% in LPK rats receiving the VDD ad libitum, and at week 20 this was associated with a mild reduction in the corrected serum calcium (SCa(2+), 7.4%) and TKW:BW ratio (8.8%), and exacerbation of proteinuria (87%) and hypertension (19%; all P < 0.05 vs. ND). When LPK rats were pair-fed for weeks 3-10, there was a further reduction in the SCa(2+) (25%) and TKW:BW ratio (22%) in the VDD group (P < 0.05 vs. ND). In study 2, the VDD did not alter food intake and body weight, reduced SCa(2+) (7.7%), worsened proteinuria (41.9%), interstitial monocyte accumulation (26.4%), renal dysfunction (21.4%), and cardiac enlargement (13.2%, all P < 0.05), but there was a trend for a reduction in the TKW:BW ratio (13%, P = 0.09). These data suggest that chronic vitamin D deficiency has adverse long-term actions on proteinuria, interstitial inflammation, renal function, and cardiovascular disease in PKD, and these negate its mild inhibitory effect on kidney enlargement.

Urinary metabonomic study of the surface layer of Poria cocos as an effective treatment for chronic renal injury in rats

Ethnopharmacological relevancePoria cocos Wolf (Polyporaceae) is a well-known medicinal fungus. The epidermis of the sclerotia (“Fu-Ling-Pi” in Chinese) is used as a diuretic and traditionally used for promoting urination and reduce edema. Aim of the studyTraditional Chinese medicines (TCM) treat many diseases through multi-components, multi-ways and multi-targets. However, the molecular mechanisms of TCM are not yet well understood. In the present work, ultra performance liquid chromatography-based metabonomics analysis was applied to investigate the urinary metabolite profiling of the renoprotective effect of FLP on adenine-induced chronic kidney disease (CKD) rat model and involved possible mechanism. Material and methodsA metabonomic approach based on ultra performance liquid chromatography coupled with quadrupole time-of-flight high-sensitivity mass spectrometry and a novel mass spectrometryElevated Energy data collection technique was developed. The resulting dataset was analyzed by principal component analysis and partial least squares discriminant analysis. The identification of all potential biomarkers was performed using reference standard by comparing their mass spectra, MSE fragments information, isotopic pattern and MassLynx i-FIT algorithm. ResultsBy partial least squares-discriminate analysis, 15 biomarkers in rat urine were identified and 11 of them were related to the pathway of adenine metabolism and amino acid metabolism. Among these biomarkers, eight biomarkers like adenine, l-acetylcarnitine, 8-hydroxyadenine, hypoxanthine, creatine, methionine, phytosphingosine and phenylalanine were reversed to the control level in FLP-treated group and six biomarkers like 2,8-dihydroxyadenine, indole-3-carboxylic acid, 3-methyldioxyindole, ethyl-N2-acetyl-l-argininate, 3-O-methyldopa and xanthurenic acid were reversed to high control group by FLP, which indicates that the urinary metabolic pattern significantly changed after FLP treatment. ConclusionsOur study indicates that FLP treatment can ameliorate CKD by intervening in some dominating metabolic pathways, such as adenine metabolism and amino acid metabolism. The metabonomic results not only supplied a systematic view of the development and progression of CKD and mechanism studies of FLP but also provided the theoretical basis for the prevention or treatment of CKD.

P02-55 Reduced epiphyseal growth plate GHR signaling in a chronic kidney disease rat model of growth retardation

P02-55 Reduced epiphyseal growth plate GHR signaling in a chronic kidney disease rat model of growth retardation

Establishment of a model of atrial fibrillation associated with chronic kidney disease in rats and the role of oxidative stress

An animal model of atrial fibrillation (AF) associated with chronic kidney disease (CKD) has not been available. The purpose of this study was to test the validity of 5/6 nephrectomy (5.6Nx) as an appropriate model of AF associated with CKD and to investigate the role of oxidative stress. Male Sprague-Dawley rats were subjected to 5.6Nx. A novel derivative of lipoic acid, sodium zinc dihydrolipoylhistidinate (DHLHZn), was subcutaneously infused. Four weeks later, hearts were isolated. We observed 5 main findings. (1) 5.6Nx induced renal dysfunction with elevation of systolic blood pressure and impaired glucose tolerance. (2) In the left atrium (LA), expressions of α-smooth muscle action and collagen type I, the compositional proteins of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and malondialdehyde were increased by 5.6Nx, which was reversed by DHLHZn treatment. (3) In the LA, the tissue content of angiotensin II was elevated by 5.6Nx, which was also reversed by DHLHZn. (4) Masson trichrome staining revealed that heterogeneous LA interstitial fibrosis was induced by 5.6Nx, which was attenuated by DHLHZn. (5) In isolated perfused heart experiments, 5.6Nx caused slowing of interatrial conduction. In the hearts of rats of the 5.6Nxgroup, right atrial extrastimuli invariably induced AF (8/8 [100%]), which were suppressed by DHLHZn (3/8 [38%], P <.05). We successfully established an appropriate model of AF associated with CKD in rats. Because the amount of NADPH oxidase was increased and the potent antioxidant agent DHLHZn was effective, oxidative stress may be involved in the pathogenesis of LA fibrosis and enhanced AF vulnerability in our model.

Protective effect of an intrinsic antioxidant, HMH (5-hydroxy-1-methylhydantoin; NZ-419), against cellular damage of kidney tubules

HMH (5-hydroxy-1-methylhydantoin; NZ-419) is a mammalian creatinine metabolite and an intrinsic antioxidant. HMH prevents the progression of chronic kidney disease in rats when a sufficient amount is taken orally. We assessed whether intrinsic and higher levels of HMH could protect tubular epithelial cells, LLC-PK(1) cells, against known cellular damage caused by xenobiotics, such as cisplatin and cephaloridine, or by hypoxia/reoxygenation treatment. Both cell damage and peroxidation, monitored as the leakage of lactate dehydrogenase (LDH) and malondialdehyde (MDA), respectively, from cells into the media, were inhibited by HMH in a concentration-dependent manner. The minimum effective concentration of HMH (2.5 μM) seemed to be too low for HMH to only be a direct hydroxyl radical scavenger. Additional antioxidant effect(s) inhibiting reactive oxygen species generation and/or modulating signal transduction pathways were suggested. The possibility that intrinsic HMH could be a protectant for the kidney was indicated. At the same time, for sufficient inhibition, higher concentrations than intrinsic HMH concentrations may be necessary. Patterns of efficacies of HMH on LDH and MDA against different kinds of cellular damage were compared with our reported data on those of corresponding, naturally occurring antioxidants. A common and specific inhibitory mechanism as well as common target(s) in kidney injuries were indicated.

Nebivolol does not protect against 5/6 ablation/infarction induced chronic kidney disease in rats — Comparison with angiotensin II receptor blockade

AimsNitric oxide (NO) deficiency contributes to chronic kidney disease progression. Nebivolol, a beta adrenergic receptor antagonist, may enhance endogenous NO. Here, we investigated whether Nebivolol attenuates hypertension and renal injury after 5/6 ablation/infarction (A/I). Efficacy was compared to the AT1 receptor antagonist Olmesartan. Main methodsKidney disease and hypertension were induced by right kidney ablation and ~2/3 infarction of the left kidney. Rats were treated orally with vehicle (placebo), Nebivolol (5mg/kg b.i.d.), or Olmesartan (2.5mg/kg/day) for 6weeks after A/I. Key findingsWith placebo, glomerular sclerosis and tubulointersititial fibrosis developed with increased blood pressure and proteinuria, and a fall in NOx excretion. Olmesartan prevented these changes, but Nebivolol had no effect on these measures but lowered heart rate. Neither treatment reduced systemic oxidative stress (urinary hydrogen peroxide and TBARS). Compared to controls, renal cortex abundance of nNOSα decreased and nNOSβ increased in rats after 5/6 A/I, with no changes in eNOS. Neither treatment restored nNOSα; however, both reduced nNOSβ. Activity of DDAH was decreased by 5/6 A/I but restored by both treatments despite no increase in DDAH protein abundance. Kidney cortex abundance of manganese SOD fell after 5/6 A/I and was restored by treatment with Olmesartan but not Nebivolol. Extracellular and copper/zinc SOD abundances were not changed. SignificanceIn conclusion, Nebivolol showed no benefit after 6weeks in rapidly progressing, ANG II-dependent 5/6 A/I model of chronic kidney disease. This contrasts to the protection seen with 6month treatment of Nebivolol in the slowly progressing 5/6 ablation model.

Pharmacological and Toxicological Advances in PPAR-Related Medicines

Pharmacological and Toxicological Advances in PPAR-Related Medicines

Alzheimer’s Disease and Retinal Neurodegeneration Share a Consistent Stress Response of the Neurovascular Unit

Background: The pathogenesis of Alzheimer’s disease (AD) is characterized by neuronal injury, activation of microglia and astrocytes, deposition of amyloid-β and secondary vessel degeneration. In the polycystic kidney disease (PKD) rat model, we observed neuronal injury, microglial activation and vasoregression. We speculated that this neuroretinal degeneration shares important pathogenetic steps with AD. Therefore, we determined the activation of astrocytes and the accumulation of amyloid-β in PKD retinae. Methods: Immunohistochemistry of PKD retinae for vimentin, carboxymethyllysin, beta-Amyloid 1-42, High-Mobility-Group- Protein B1 and amyloid protein precursor was performed. Results: Adjunct to astrocyte activation, accumulation of beta-Amyloid 1-42 and High-Mobility-Group-Protein B1 in astrocytes and around vessels of the superficial network was found in PKD retinae prior to the onset of vasoregression. Amyloid precursor protein was localized adjacent to the outer segment of photoreceptors in PKD and control rats. The parallel appearance of AD-related peptides indicates an alarmine based response to photoreceptor degeneration and secondary vasoregression. Conclusion: The model has broad overlap with AD and may be suitable to study beneficial pharmacological concepts.

Dietary phosphate restriction ameliorates endothelial dysfunction in adenine-induced kidney disease rats

Hyperphosphatemia causes endothelial dysfunction as well as vascular calcification. Management of serum phosphate level by dietary phosphate restriction or phosphate binders is considered to be beneficial to prevent chronic kidney disease patients from cardiovascular disease, but it has been unclear whether keeping lower serum phosphate level can ameliorate endothelial dysfunction. In this study we investigated whether low-phosphate diet can ameliorate endothelial dysfunction in adenine-induced kidney disease rats, one of useful animal model of chronic kidney disease. Administration of 0.75% adenine-containing diet for 21 days induced renal failure with hyperphosphatemia, and impaired acetylcholine-dependent vasodilation of thoracic aortic ring in rats. Then adenine-induced kidney disease rats were treated with either control diet (1% phosphate) or low-phosphate diet (0.2% phosphate) for 16 days. Low-phosphate diet ameliorated not only hyperphosphatemia but also the impaired vasodilation of aorta. In addition, the activatory phosphorylation of endothelial nitric oxide synthase at serine 1177 and Akt at serine 473 in the aorta were inhibited by in adenine-induced kidney disease rats. The inhibited phosphorylations were improved by the low-phosphate diet treatment. Thus, dietary phosphate restriction can improve aortic endothelial dysfunction in chronic kidney disease with hyperphosphatemia by increase in the activatory phosphorylations of endothelial nitric oxide synthase and Akt.

AST-120 Ameliorates Epithelial-to-Mesenchymal Transition and Interstitial Fibrosis in the Kidneys of Chronic Kidney Disease Rats

Indoxyl sulfate (IS), a uremic toxin, is a risk factor for progression of chronic kidney disease (CKD). AST-120 reduces serum IS and delays the progression of CKD. This study aimed to examine whether AST-120 inhibits epithelial-to-mesenchymal transition (EMT) in the kidneys of CKD rats. CKD rats were produced by 5/6 nephrectomy and were divided into 2 groups: (1) CKD rats and (2) AST-120-treated CKD rats at a dosage of 4 g/kg body weight/day. After 10 weeks, their kidneys were excised for histological and immunohistochemical analysis. EMT was evaluated by immunohistochemistry of zonula occludens (ZO-1), an epithelial marker, and alpha-smooth muscle actin (α-SMA), a mesenchymal marker. Interstitial fibrosis was evaluated by Masson's trichrome staining. CKD rats showed reduced expression of ZO-1 and enhanced expression of α-SMA as compared with normal rats. Administration of AST-120 to CKD rats increased expression of ZO-1 and decreased expression of α-SMA as compared with CKD rats. Further, CKD rats showed enhanced extent of interstitial fibrosis as compared with normal rats, and administration of AST-120 to CKD rats ameliorated interstitial fibrosis. CKD rats showed increased serum level of IS as compared with normal rats, whereas administration of AST-120 to CKD rats decreased both serum and urine levels of IS. We conclude that AST-120 ameliorated EMT and interstitial fibrosis in the kidneys of CKD rats, probably by alleviating IS overload on the kidneys.

Metabolomic profiling of the autosomal dominant polycystic kidney disease rat model

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited systemic disease characterized by renal cyst expansion, resulting in renal failure. With the progression of renal damage, the accumulation of uremic compounds is recently reported to subsequently cause further renal damage and hypertension. Finding uremic toxins and sensitive markers for detecting the early stage of ADPKD is necessary to clarify its pathophysiological process and to prevent its progression. The aim of this study was to analyze the profile of uremic retention solutes of ADPKD by capillary electrophoresis-mass spectrometry (CE-MS) using the Han:SPRD rat model. Two hundred and ninety-seven cations and 190 anions were comprehensively analyzed by CE-MS in Han:SPRD rats and control rats. We found 21 cations and 19 anions that accumulated significantly in the heterozygous (Cy/+) ADPKD rat model compared with control rats. Among the compounds, increases in 5-methyl-2'-deoxycytidine, glucosamine, ectoine, allantoate, α-hydroxybenzoate, phenaceturate and 3-phenylpropionate and decreases in 2-deoxycytidine, decanoate and 10-hydroxydecanoate were newly identified in the ADPKD Cy/+ rats. We identified uremic retention solutes in ADPKD Cy/+ rats. Compounds related to ADPKD could be useful markers for detecting the early stage of ADPKD.

Leucine-stimulated mTOR signaling is partly attenuated in skeletal muscle of chronically uremic rats

The branched-chain amino acid leucine stimulates muscle protein synthesis in part by directly activating the mTOR signaling pathway. Furthermore, leucine, if given in conjunction with resistance exercise, enhances the exercise-induced mTOR signaling and protein synthesis. Here we tested whether leucine can activate the mTOR anabolic signaling pathway in uremia and whether it can enhance work overload (WO)-induced signaling through this pathway. Chronic kidney disease (CKD) and control rats were studied after 7 days of surgically induced unilateral plantaris muscle WO and a single leucine or saline load. In the basal state, 4E-BP1 phosphorylation was modestly depressed in non-WO muscle of CKD rats, whereas rpS6 phosphorylation was nearly completely suppressed. After oral leucine mTOR, S6K1 and rpS6 phosphorylation increased similarly in both groups, whereas the phospho-4E-BP1 response was modestly attenuated in CKD. WO alone activated the mTOR signaling pathway in control and CKD rats. In WO CKD, muscle leucine augmented mTOR and 4E-BP1 phosphorylation, but its effect on S6K1 phosphorylation was attenuated. Taken together, this study has established that the chronic uremic state impairs basal signaling through the mTOR anabolic pathway, an abnormality that may contribute to muscle wasting. However, despite this abnormality, leucine can stimulate this signaling pathway in CKD, although its effectiveness is partially attenuated, including in skeletal muscle undergoing sustained WO. Thus, although there is some resistance to leucine in CKD, the data suggest a potential role for leucine-rich supplements in the management of uremic muscle wasting.

Aortic stiffness is associated with vascular calcification and remodeling in a chronic kidney disease rat model

Increased aortic pulse-wave velocity (PWV) reflects increased arterial stiffness and is a strong predictor of cardiovascular risk in chronic kidney disease (CKD). We examined functional and structural correlations among PWV, aortic calcification, and vascular remodeling in a rodent model of CKD, the Lewis polycystic kidney (LPK) rat. Hemodynamic parameters and beat-to-beat aortic PWV were recorded in urethane-anesthetized animals [12-wk-old hypertensive female LPK rats (n = 5)] before the onset of end-stage renal disease and their age- and sex-matched normotensive controls (Lewis, n = 6). Animals were euthanized, and the aorta was collected to measure calcium content by atomic absorption spectrophotometry. A separate cohort of animals (n = 5/group) were anesthetized with pentobarbitone sodium and pressure perfused with formalin, and the aorta was collected for histomorphometry, which allowed calculation of aortic wall thickness, medial cross-sectional area (MCSA), elastic modulus (EM), and wall stress (WS), size and density of smooth muscle nuclei, and relative content of lamellae, interlamellae elastin, and collagen. Mean arterial pressure (MAP) and PWV were significantly greater in the LPK compared with Lewis (72 and 33%, respectively) animals. The LPK group had 6.8-fold greater aortic calcification, 38% greater aortic MCSA, 56% greater EM/WS, 13% greater aortic wall thickness, 21% smaller smooth muscle cell area, and 20% less elastin density with no difference in collagen fiber density. These findings demonstrate vascular remodeling and increased calcification with a functional increase in PWV and therefore aortic stiffness in hypertensive LPK rats.

Novel Lipoic Acid Derivative Drug Prevents Atrial Fibrosis and Fibrillation Associated with Chronic Kidney Disease in Rats

Novel Lipoic Acid Derivative Drug Prevents Atrial Fibrosis and Fibrillation Associated with Chronic Kidney Disease in Rats

Genomic damage in the progression of chronic kidney disease in rats

Patients with chronic renal failure exhibit massive oxidative genome damage and an elevated risk of cancer. Previous studies have demonstrated the relationship between DNA damage and carcinogenesis. The current study aimed to investigate whether the progression of chronic kidney disease induces genomic damage in an animal model. Adult Wistar rats were assigned to either the control or chronic kidney disease groups. The chronic kidney disease group was subdistributed into five groups with progressively longer durations of disease (30, 60, 90, 120 and 150days). The results showed that chronic kidney disease induced genomic damage in the blood, liver and kidney cells during all periods evaluated, as indicated by the mean tail moment measured in the comet assay. In brain cells, no genetic damage was induced at early/intermediate disease durations; however, positive genotoxicity was found at 120 and 150days. Blood pressure and pro-inflammatory cytokine levels (IL-1α, IL-1β, IL-6 and TNFα) were increased after chronic kidney disease induction, while blood iron concentration was significantly reduced in these animals. The results suggest that chronic kidney disease progression contributes to DNA damage in blood, liver, kidney and brain and that such damage can be mediated by hypertension, an inflammatory status and iron deficiency. Additionally, the brain was sensitive to genotoxic insult after extended chronic kidney disease, suggesting a potentially important role of genetic damage in the neurological disorders of end-stage renal patients.