scholarly journals Loss of ischemic tolerance with age: can we protect an old kidney

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 690-690
Author(s):  
Egor Plotnikov
Keyword(s):  
Kidney Tissue ◽  
Kidney Injury ◽  
Ischemic Tolerance ◽  
Proliferative Potential ◽  
Russian Science ◽  
Mitochondrial Quality Control ◽  
Defense Systems ◽  
Old Rats ◽  
Loss Of Tolerance ◽  
Aging Kidney

Abstract The most abundant and vulnerable cohort of patients with acute kidney injury (AKI) is represented by the older people. It is well-known, the kidney tissue undergoes some changes with age, both at the morphological and molecular level. Therefore, when treating AKI in older patients, it is necessary to take into account the morphofunctional features of aging kidney tissue and metabolic alterations. We have shown that the kidney of old rats does not perceive signals from the most well-known protective approaches such as ischemic preconditioning (IPC) and caloric restriction (CR). Although the old kidney did not develop more severe AKI after ischemia, we found no pronounced effect on attempts to increase its resistance by IPC and CR. Analysis of the mechanisms underlying this loss of tolerance has shown that the most affected pathways are the mechanism of mitochondrial quality control, the effectiveness of autophagy, and the proliferative potential of kidney cells. However, several protective pathways activated in the young kidney were also active in the old one in response to the CR. In particular, an increase in SIRT1 deacetylase, antiapoptotic Bcl-xL, and a decrease in oxidative stress were observed. Our results show that some defense systems demonstrating their effectiveness in young organisms lose their beneficial effect in old organisms, while others still can be activated by protective approaches. Thus, it is necessary to carefully analyze the possibilities of increasing ischemic tolerance for old organisms. This work was supported by the Russian science foundation (grant #21-75-30009).

scholarly journals P0529THE DIFFERENCE IN DIETARY RESTRICTION-INDUCED NEPHROPROTECTIVE MECHANISMS IN YOUNG AND OLD ANIMALS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Nadezda Andrianova ◽  
Ljubava Zorova ◽  
Irina Pevzner ◽  
Vasily Popkov ◽  
Denis Silachev ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Dietary Restriction ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Male Rats ◽  
Kidney Cells ◽  
Lipid Peroxidation Products ◽  
Kidney Slices ◽  
Young Rats ◽  
Old Rats

Abstract Background and Aims Acute kidney injury (AKI) is a widespread disease affecting mostly old people. Dietary restriction (DR), based on the reduction of food intake, is believed to be one of the most efficient approaches ameliorating damage in different pathological conditions including age-associated diseases. The aim of the study was to investigate the protective mechanisms of DR in the model of AKI in young and old rats. Method All experiments were made on young (3-4 months) and old (22-24 months) male rats. DR was performed by limiting the amount of food for 35% of the ad libitum (AL) daily intake. Since earlier, we showed ineffectiveness of 4-weeks DR in old rats, in this study we applied 35% DR lasting 8 weeks for old rats and 4 weeks for young rats. During DR, we registered the weight loss and measured the level of adiponectin, as this hormone is closely associated with adipose tissue metabolism. Renal ischemia/reperfusion (I/R) was used as a model of ischemic AKI. I/R was performed by clamping the left renal pedicle for 40 minutes followed by reperfusion with simultaneous contralateral nephrectomy. The severity of AKI was evaluated by measuring blood urea nitrogen (BUN), serum creatinine (SCr) and the levels of protein biomarkers of AKI (NGAL and L-FABP) in urine. Proliferation in kidney epithelium in response to I/R was analyzed by PCNA protein level in kidney tissue. We evaluated the function of mitochondria by measuring TMRE/MitoTracker Green ratio in vital kidney slices; in kidney homogenates, we also analyzed levels of Bcl-XL and Bcl-XS proteins. The production of reactive oxygen species (ROS) was evaluated by staining vital kidney slices with DCF. The content of lipid peroxidation products was measured using Image-iT Lipid Peroxidation Kit, and the level of carbonylated proteins was determined by OxyBlot Protein Oxidation Detection Kit. The activation of autophagic-lysosomal system was estimated by western blotting to LC3 II/LC3 I ratio and LAMP1 level, as well as by staining vital kidney slices with LysoTracker Green probe. Results The body weight of rats during DR dropped as far as 20% by the end of 4 weeks in young rats and 30% by the end of 8 weeks in old rats. Nevertheless, adiponectin concentration elevated during DR only in the serum of young rats. DR strongly influenced mitochondria function, in particular, elevated mitochondrial membrane potential both in kidney cells of young and old rats. DR also resulted in increasing the Bcl-XL level. We revealed the decrease of ROS and lipid peroxidation products in vital kidney slices, but only in kidneys of young rats. However, DR reduced the content of carbonyl groups more than 2 times in animals of both ages. We showed that activation of autophagy in response to DR and I/R occurred only in the kidneys of young rats, indicating deterioration of autophagy signaling in old animals. We also found that 48 h after I/R PCNA level increased 19 times in young kidney, although old rats showed only 4-fold elevation of kidney cells proliferation. Estimation of kidney injury markers (NGAL, L-FABP) in urine revealed that 2-month DR led to some protection in old rats. Nonetheless, despite all positive alterations in kidney tissue of old rats, DR was not able to ameliorate impairment of kidney function after I/R, whereas all young rats showed significant improvement of SCr and BUN levels. Conclusion Short-term DR has a significant nephroprotective effect against renal I/R in young rats. Old animals require longer periods of food restriction, after which some protective alterations are observed. We propose, protection of kidney in old and young rats is implemented through slightly different mechanisms and some of them are missing in old animals.

scholarly journals Mechanisms of Age-Dependent Loss of Dietary Restriction Protective Effects in Acute Kidney Injury

Cells ◽  
2018 ◽  
Vol 7 (10) ◽  
pp. 178 ◽  
Author(s):  
Nadezda V. Andrianova ◽  
Stanislovas S. Jankauskas ◽  
Ljubava D. Zorova ◽  
Irina B. Pevzner ◽  
Vasily A. Popkov ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Dietary Restriction ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Protective Effects ◽  
Renal Cells ◽  
Mitochondria Membrane Potential ◽  
Lipofuscin Granules ◽  
Rate Of Recovery ◽  
Old Rats

Dietary restriction (DR) is one of the most efficient approaches ameliorating the severity of different pathological conditions including aging. We investigated the protective potential of short-term DR in the model of acute kidney injury (AKI) in young and old rats. In kidney tissue, the levels of autophagy and mitophagy were examined, and proliferative properties of renal cells obtained from rats of different age were compared. DR afforded a significant nephroprotection to ischemic kidneys of young rats. However, in old rats, DR did not provide such beneficial effect. On the assessment of the autophagy marker, the LC3 II/LC3 I ratio, and after staining the tissue with LysoTracker Green, we concluded that in old rats activity of the autophagic-lysosomal system decreased. Mitophagy, as assessed by the levels of PINK-1, was also deteriorated in old animals. Renal cells from old rats showed impaired proliferative capacity, a worse rate of recovery after ischemic injury, increased levels of oxidative stress, accumulation of lipofuscin granules and lower mitochondria membrane potential. The results suggest that the loss of DR benefits in old animals could be due to deterioration in the autophagy/mitophagy flux.

scholarly journals The Encapsulation of Lycopene in Nanoliposomes Enhances Its Protective Potential in Methotrexate-Induced Kidney Injury Model

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Nenad Stojiljkovic ◽  
Sonja Ilic ◽  
Vladimir Jakovljevic ◽  
Nikola Stojanovic ◽  
Slavica Stojnev ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Structural Changes ◽  
Corn Oil ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Serum Urea ◽  
Morphological Alterations ◽  
Injury Model ◽  
Serum Biochemical ◽  
Degree Of Recovery

Methotrexate is an antimetabolic drug with a myriad of serious side effects including nephrotoxicity, which presumably occurs due to oxidative tissue damage. Here, we evaluated the potential protective effect of lycopene, a potent antioxidant carotenoid, given in two different pharmaceutical forms in methotrexate-induced kidney damage in rats. Serum biochemical (urea and creatinine) and tissue oxidative damage markers and histopathological kidney changes were evaluated after systemic administration of both lycopene dissolved in corn oil and lycopene encapsulated in nanoliposomes. Similar to previous studies, single dose of methotrexate induced severe functional and morphological alterations of kidneys with cell desquamation, tubular vacuolation, and focal necrosis, which were followed by serum urea and creatinine increase and disturbances of tissue antioxidant status. Application of both forms of lycopene concomitantly with methotrexate ameliorated changes in serum urea and creatinine and oxidative damage markers and markedly reversed structural changes of kidney tissue. Moreover, animals that received lycopene in nanoliposome-encapsulated form showed higher degree of recovery than those treated with free lycopene form. The findings of this study indicate that treatment with nanoliposome-encapsulated lycopene comparing to lycopene in standard vehicle has an advantage as it more efficiently reduces methotrexate-induced kidney dysfunction.

scholarly journals Extracellular vesicles as immune mediators in response to kidney injury

2018 ◽  
Vol 314 (1) ◽  
pp. F9-F21 ◽  
Author(s):  
Eva Feigerlová ◽  
Shyue-Fang Battaglia-Hsu ◽  
Thierry Hauet ◽  
Jean-Louis Guéant
Keyword(s):  
Extracellular Vesicles ◽  
Therapeutic Potential ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Bioactive Molecules ◽  
Renal Diseases ◽  
Cytokine Signaling ◽  
Renal Tubular ◽  
Tissue Recovery

Important progress has been made on cytokine signaling in response to kidney injury in the past decade, especially cytokine signaling mediated by extracellular vesicles (EVs). For example, EVs released by injured renal tubular epithelial cells (TECs) can regulate intercellular communications and influence tissue recovery via both regulating the expression and transferring cytokines, growth factors, as well as other bioactive molecules at the site of injury. The effects of EVs on kidney tissue seem to vary depending on the sources of EVs; however, the literature data are often inconsistent. For example, in rodents EVs derived from mesenchymal stem cells (MSC-EVs) and endothelial progenitor cells (EPC-EVs) can have both beneficial and harmful effects on injured renal tissue. Caution is thus needed in the interpretation of these data as contradictory findings on EVs may not only be related to the origin of EVs, they can also be caused by the different methods used for EV isolation and the physiological and pathological states of the tissues/cells under which they were obtained. Here, we review and discuss our current understanding related to the immunomodulatory function of EVs in renal tubular repair in the hope of encouraging further investigations on mechanisms related to their antiinflammatory and reparative role to better define the therapeutic potential of EVs in renal diseases.

scholarly journals Antioxidant Activity, Phenolic Profile, and Nephroprotective Potential of Anastatica hierochuntica Ethanolic and Aqueous Extracts against CCl4-Induced Nephrotoxicity in Rats

Nutrients ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2973
Author(s):  
Tariq I. Almundarij ◽  
Yousef M. Alharbi ◽  
Hassan A. Abdel-Rahman ◽  
Hassan Barakat
Keyword(s):  
Oxidative Stress ◽  
Antioxidant Activity ◽  
Therapeutic Agent ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Total Phenolic ◽  
Drug Induced ◽  
Total Carotenoids ◽  
Phenolic Profile ◽  
Better Than

Kaff-e-Maryam (Anastatica hierochuntica L.) is extensively used to treat a range of health problems, most notably to ease childbirth and alleviate reproductive system-related disorders. This study aimed to evaluate the effect of A. hierochuntica ethanolic (KEE), and aqueous (KAE) extracts on CCl4-induced oxidative stress and nephrotoxicity in rats using the biochemical markers for renal functions and antioxidant status as well as histopathological examinations of kidney tissue. A. hierochuntica contained 67.49 mg GAE g−1 of total phenolic compounds (TPC), 3.51 µg g−1 of total carotenoids (TC), and 49.78 and 17.45 mg QE g−1 of total flavonoids (TF) and total flavonols (TFL), respectively. It resulted in 128.71 µmol of TE g−1 of DPPH-RSA and 141.92 µmol of TE g−1 of ABTS-RSA. A. hierochuntica presented superior antioxidant activity by inhibiting linoleic acid radicals and chelating oxidation metals. The HPLC analysis resulted in 9 and 21 phenolic acids and 6 and 2 flavonoids in KEE and KAE with a predominance of sinapic and syringic acids, respectively. Intramuscular injection of vit. E + Se and oral administration of KEE, KAE, and KEE + KAE at 250 mg kg−1 body weight significantly restored serum creatinine, urea, K, total protein, and albumin levels. Additionally, they reduced malondialdehyde (MOD), restored reduced-glutathione (GSH), and enhanced superoxide dismutase (SOD) levels. KEE, KAE, and KEE + KAE protected the kidneys from CCl4-nephrotoxicity as they mainly attenuated induced oxidative stress. Total nephroprotection was about 83.27%, 97.62%, and 78.85% for KEE, KAE, and KEE + KAE, respectively. Both vit. E + Se and A. hierochuntica extracts attenuated the histopathological alteration in CCl4-treated rats. In conclusion, A. hierochuntica, especially KAE, has the potential capability to restore oxidative stability and improve kidney function after CCl4 acute kidney injury better than KEE. Therefore, A. hierochuntica has the potential to be a useful therapeutic agent in the treatment of drug-induced nephrotoxicity.

scholarly journals Immunopathogenesis of Acute Kidney Injury

2018 ◽  
Vol 46 (8) ◽  
pp. 930-943 ◽  
Author(s):  
Zaher A. Radi
Keyword(s):  
Acute Kidney Injury ◽  
T Cells ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Drug Induced ◽  
Inflammatory Damage ◽  
Anti Inflammatory ◽  
Renal Tubular ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Pathophysiologically, the classification of acute kidney injury (AKI) can be divided into three categories: (1) prerenal, (2) intrinsic, and (3) postrenal. Emerging evidence supports the involvement of renal tubular epithelial cells and the innate and adaptive arms of the immune system in the pathogenesis of intrinsic AKI. Pro-inflammatory damage-associated molecular patterns, pathogen-associated molecular patterns, hypoxia inducible factors, toll-like receptors, complement system, oxidative stress, adhesion molecules, cell death, resident renal dendritic cells, neutrophils, T and B lymphocytes, macrophages, natural killer T cells, cytokines, and secreted chemokines contribute to the immunopathogenesis of AKI. However, other immune cells and pathways such as M2 macrophages, regulatory T cells, progranulin, and autophagy exhibit anti-inflammatory properties and facilitate kidney tissue repair after AKI. Thus, therapies for AKI include agents such as anti-inflammatory (e.g., recombinant alkaline phosphatase), antioxidants (iron chelators), and apoptosis inhibitors. In preclinical toxicity studies, drug-induced kidney injury can be seen after exposure to a nephrotoxicant test article due to immune mechanisms and dysregulation of innate, and/or adaptive cellular immunity. The focus of this review will be on intrinsic AKI, as it relates to the immune and renal systems cross talks focusing on the cellular and pathophysiologic mechanisms of AKI.

Glomerular filtration, renal blood flow, and solute excretion in conscious aging rats

1987 ◽  
Vol 253 (4) ◽  
pp. R555-R560 ◽  
Author(s):  
B. Corman ◽  
J. B. Michel
Keyword(s):  
Glomerular Filtration ◽  
Filtration Rate ◽  
Age Groups ◽  
Kidney Tissue ◽  
Female Rats ◽  
Daily Food ◽  
Moderate Volume ◽  
Old Rats ◽  
Magnesium Excretion ◽  
Solute Excretion

Measurement of daily food and water intakes and of renal water and solute excretion in 10-, 20-, and 30-mo-old female rats revealed that they ate the same amounts of food and excreted the same amounts of glucose, sodium, and potassium irrespective of age but that in the 30-mo-old rats phosphate, calcium, and magnesium excretion rose. The glomerular filtration rate and p-aminohippuric acid clearance measured in conscious animals following moderate volume expansion did not differ with age, when expressed per 100 g body wt, but decreased markedly in the 30-mo-old rats when compared with kidney weight. This was related to the senile hypertrophy of the kidneys in the 30-mo-old group, which was reflected by increases in glomerular volume and length of the proximal tubules and by enlargement of the medulla, with the number of nephrons remaining constant with age. There was no evidence of glomerulosclerosis or kidney disease, and proteinuria remained at a low level in all three age groups. These results suggest that the diminished renal filtration rate observed in both conscious and anesthetized senescent rats is due to a reduced supply of blood per gram of kidney tissue and not to loss of nephrons.

scholarly journals Ameliorating Effect of Pentadecapeptide Derived from Cyclina sinensis on Cyclophosphamide-Induced Nephrotoxicity

Marine Drugs ◽  
2020 ◽  
Vol 18 (9) ◽  
pp. 462
Author(s):  
Xiaoxia Jiang ◽  
Zhexin Ren ◽  
Biying Zhao ◽  
Shuyao Zhou ◽  
Xiaoguo Ying ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Antioxidant Enzymes ◽  
Glutathione Peroxidase ◽  
Anticancer Drug ◽  
Tissue Damage ◽  
Kidney Tissue ◽  
Kidney Injury ◽  
Inflammatory Factors ◽  
Cyclina Sinensis ◽  
Apoptotic Pathways

Cyclophosphamide (CTX) is a widely used anticancer drug with severe nephrotoxicity. The pentadecapeptide (RVAPEEHPVEGRYLV) from Cyclina sinensis (SCSP) has been shown to affect immunity and to protect the liver. Hence, the purpose of this study was to investigate the ameliorating effect of SCSP on CTX-induced nephrotoxicity in mice. We injected male ICR mice with CTX (80 mg/kg·day) and measured the nephrotoxicity indices, levels of antioxidant enzymes, malondialdehyde (MDA), inflammatory factors, as well as the major proteins of the NF-κB and apoptotic pathways. Cyclophosphamide induced kidney injury; the levels of kidney-injury indicators and cytokines recovered remarkably in mice after receiving SCSP. The activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) increased, while there was a significant decrease in MDA levels. The kidney tissue damage induced by CTX was also repaired to a certain extent. In addition, SCSP significantly inhibited inflammatory factors and apoptosis by regulating the NF-κB and apoptotic pathways. Our study shows that SCSP has the potential to ameliorate CTX-induced nephrotoxicity and may be used as a therapeutic adjuvant to ameliorate CTX-induced nephrotoxicity.

Renal tubular Notch signaling triggers a prosenescent state after acute kidney injury

2014 ◽  
Vol 306 (8) ◽  
pp. F907-F915 ◽  
Author(s):  
Inga Sörensen-Zender ◽  
Song Rong ◽  
Nathan Susnik ◽  
Steffen Zender ◽  
Petra Pennekamp ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Ischemia Reperfusion ◽  
Butyl Ester ◽  
Kidney Injury ◽  
Acute Injury ◽  
Tubular Damage ◽  
Tubular Atrophy ◽  
Aging Kidney ◽  
Notch Activation

The aging kidney has a diminished regenerative potential and an increased tendency to develop tubular atrophy and fibrosis after acute injury. In this study, we found that activation of tubular epithelial Notch1 signaling was prolonged in the aging kidney after ischemia/reperfusion (IR) damage. To analyze the consequences of sustained Notch activation, we generated mice with conditional inducible expression of Notch1 intracellular domain (NICD) in proximal tubules. NICD kidneys were analyzed 1 and 4 wk after renal IR. Conditional NICD expression was associated with aggravated tubular damage, a fibrotic phenotype, and the expression of cellular senescence markers p21 and p16 INK4a. In wild-type mice pharmacological inhibition of Notch using the γ-secretase inhibitor N-[ N-(3,5-difluorophenacetyl)-l-alanyl]- S-phenylglycine t-butyl ester (DAPT) improved tubulo-interstitial damage and antagonized the prosenescent pathway activation after IR. In vitro, activation of Notch signaling with delta-like-ligand-4 caused prosenescent changes in tubular cells while inhibition with DAPT attenuated these changes. In conclusion, our data suggest that sustained epithelial Notch activation after IR might contribute to the inferior outcome of old kidneys after injury. Sustained epithelial activation of Notch is associated with a prosenescent phenotype and maladaptive repair.

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