scholarly journals Dynamics of GRK2 in the kidney: a putative mechanism for sepsis-associated kidney injury

2021 ◽  
Author(s):  
Thiele Osvaldt Rosales ◽  
Verônica Vargas Horewicz ◽  
Marcella Amorim Ferreira ◽  
Geisson Marcos Nardi ◽  
Jamil Assreuy
Keyword(s):  
Adrenergic Receptor ◽  
Vascular Reactivity ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Systemic Circulation ◽  
Receptor Density ◽  
No Donor ◽  
In Vivo Experiments ◽  
Renal Vascular

Renal vascular reactivity to vasoconstrictors is preserved in sepsis in opposition to what happens in the systemic circulation. We studied whether this distinct behavior was related to α1 adrenergic receptor density, G protein-coupled receptor kinase 2 (GRK2) and the putative role of nitric oxide (NO). Sepsis was induced in female mice by cecal ligation and puncture (CLP). Wild-type mice were treated with prazosin 12 hours after CLP or NOS-2 inhibitor, 30 min before and 6 and 12 hours after CLP. In vivo experiments and biochemistry assays were performed 24 hours after CLP. Sepsis decreased the systemic mean arterial pressure and the vascular reactivity to phenylephrine. Sepsis also reduced basal renal blood flow which was normalized by treatment with prazosin. Sepsis led to a substantial decreased in GRK2 level associated to an increase in α1 adrenergic receptor density in the kidney. The disappearance of renal GRK2 was prevented in NOS-2-KO mice or mice treated with 1400W. Treatment of non-septic mice with a NO donor reduced GRK2 content in the kidney. Therefore, our results show that a NO-dependent reduction in GRK2 level in the kidney leads to the maintenance of a normal α1 adrenergic receptor density, probably. The preservation of the density and/or functionality of this receptor in the kidney together with a higher vasoconstrictor tonus in sepsis lead to vasoconstriction. Thus, the increased concentration of vasoconstrictor mediators together with the preservation (and even increase) of the response to them may help to explain sepsis-induced acute kidney injury.

Stem Cell Cure for Kidney Injury: Therapy to Solve Most Complex Issues in Renal System

2020 ◽  
Author(s):  
Prithiv K R Kumar
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Kidney Injury ◽  
Cell Types ◽  
Tissue Remodelling ◽  
Major Health Problem ◽  
In Vivo Experiments ◽  
Renal Regeneration ◽  
Induced Pluripotent

Renal failure is a major health problem. The mortality rate remain high despite of several therapies. The most complex of the renal issues are solved through stem cells. In this review, different mechanism for cure of chronic kidney injury along with cell engraftment incorporated into renal structures will be analysed. Paracrine activities of embryonic or induced Pluripotent stem cells are explored on the basis of stem cell-induced kidney regeneration. Several experiments have been conducted to advance stem cells to ensure the restoration of renal functions. More vigour and organised protocols for delivering stem cells is a possibility for advancement in treatment of renal disease. Also there is a need for pressing therapies to replicate the tissue remodelling and cellular repair processes suitable for renal organs. Stem cells are the undifferentiated cells that have the ability to multiply into several cell types. In vivo experiments on animal’s stem cells have shown significant improvements in the renal regeneration and functions of organs. Nevertheless more studies show several improvements in the kidney repair due to stem cell regeneration.

α2-Adrenoceptor agonist dexmedetomidine protects septic acute kidney injury through increasing BMP-7 and inhibiting HDAC2 and HDAC5

2012 ◽  
Vol 303 (10) ◽  
pp. F1443-F1453 ◽  
Author(s):  
Chung-Hsi Hsing ◽  
Chiou-Feng Lin ◽  
Edmund So ◽  
Ding-Ping Sun ◽  
Tai-Chi Chen ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Histone H3 ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Protective Effects ◽  
Tnf Α

Bone morphogenetic protein (BMP)-7 protects sepsis-induced acute kidney injury (AKI). Dexmedetomidine (DEX), an α2-adrenoceptor (α2-AR) agonist, has anti-inflammatory effects. We investigated the protective effects of DEX on sepsis-induced AKI and the expression of BMP-7 and histone deacetylases (HDACs). In vitro , the effects of DEX or trichostatin A (TSA, an HDAC inhibitor) on TNF-α, monocyte chemotactic protein (MCP-1), BMP-7, and HDAC mRNA expression in LPS-stimulated rat renal tubular epithelial NRK52E cells, was determined using real-time PCR. In vivo, mice were intraperitoneally injected with DEX (25 μg/kg) or saline immediately and 12 h after cecal ligation and puncture (CLP) surgery. Twenty-four hours after CLP, we examined kidney injury and renal TNF-α, MCP-1, BMP-7, and HDAC expression. Survival was monitored for 120 h. LPS increased HDAC2, HDAC5, TNF-α, and MCP-1 expression, but decreased BMP-7 expression in NRK52E cells. DEX treatment decreased the HDAC2, HDAC5, TNF-α, and MCP-1 expression, but increased BMP-7 and acetyl histone H3 expression, whose effects were blocked by yohimbine, an α2-AR antagonist. With DEX treatment, the LPS-induced TNF-α expression and cell death were attenuated in scRNAi-NRK52E but not BMP-7 RNAi-NRK52E cells. In CLP mice, DEX treatment increased survival and attenuated AKI. The expression of HDAC2, HDAC5, TNF-α, and MCP-1 mRNA in the kidneys of CLP mice was increased, but BMP-7 was decreased. However, DEX treatment reduced those changes. DEX reduces sepsis-induced AKI by decreasing TNF-α and MCP-1 and increasing BMP-7, which is associated with decreasing HDAC2 and HDAC5, as well as increasing acetyl histone H3.

Role of endothelium-derived relaxing factors in the renal response to vasoactive agents in hypothyroid rats

2003 ◽  
Vol 285 (1) ◽  
pp. E182-E188 ◽  
Author(s):  
Juan Manuel Moreno ◽  
Rosemary Wangensteen ◽  
Juan Sainz ◽  
Isabel Rodríguez-Gomez ◽  
Virginia Chamorro ◽  
...  
Keyword(s):  
Vascular Reactivity ◽  
Ang Ii ◽  
Vasoactive Agents ◽  
Normal Response ◽  
No Donor ◽  
Increased Sensitivity ◽  
Renal Vascular ◽  
And Control ◽  
Renal Responses

This study analyzed the role of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) in the abnormal renal vascular reactivity of hypothyroid rats. Renal responses to vasoconstrictors [VC: phenylephrine (PHE) and ANG II] and vasodilators [VD: ACh, sodium nitroprusside (SNP), and papaverine (PV)] were studied in kidneys from control and hypothyroid rats under normal conditions and after NO or EDHF blockade. NO was blocked by the administration of Nω-nitro-l-arginine methyl ester (l-NAME) and EDHF by the administration of tetraethylammonium (TEA) or by an increased extracellular K+. The response to VC was also evaluated after endothelium removal. Hypothyroid kidneys showed reduced responsiveness to PHE and a normal response to ANG II. l-NAME and TEA administration produced an increased sensitivity to PHE and to ANG II in control preparations. l-NAME also increased the response to PHE in hypothyroid kidneys, but the differences between control and hypothyroid kidneys were maintained. TEA administration did not change the response to either VC in hypothyroid preparations. In endothelium-removed preparations, TEA was unable to increase pressor responsiveness to VC. Hypothyroid kidneys showed reduced responsiveness to ACh and SNP and normal response to PV. The differences between hypothyroid and control preparations in the responses to ACh and SNP were maintained after l-NAME or increased K+. In conclusion, this study shows that 1) the attenuated response to PHE in hypothyroidism is not related to an increased production of endothelium-derived relaxing factors NO and EDHF; 2) the response to VC in hypothyroid preparations is insensitive to EDHF blockade; and 3) hypothyroid preparations have a reduced reactivity to the NO donor, and NO-independent vasodilatation remains unaffected.

scholarly journals TRPV4-mediated Ca2+ influx is essential to glomerular endothelial inflammation in sepsis associated acute kidney injury

2021 ◽  
Author(s):  
Xia Wang ◽  
Yinhua Wang ◽  
Guo Zhou ◽  
Yi Li ◽  
Huanhuan Huo ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Endothelial Cells ◽  
Cell Injury ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Blood Perfusion ◽  
High Morbidity ◽  
Endothelial Inflammation ◽  
Glomerular Endothelial Cells

Abstract Background Sepsis-associated acute kidney injury (S-AKI) is a frequent complication of critical patients and is associated with high morbidity and mortality. The glomerular endothelial cell injury is the main characteristics during S-AKI. Ca2+ influx is a key step in the establishment of endothelial injury. Transient receptor vanilloid subtype 4 (TRPV4) ion channels are permeable to Ca2+ and are widely expressed in endothelial cells. However, the role of TRPV4 on glomerular endothelial inflammation in S-AKI has remained elusive. Methods Mouse glomerular endothelial cells (MRGEC) were used to test the molecular mechanism of TRPV4 on LPS-induced glomerular endothelial inflammation. The cecal-ligation-and-puncture (CLP) model was established by ligation of cecum with 4-0 suture and punctured with a 21-gauge needle. Then 0.2mL faeces was extruded from the puncture site to trigger peritoneal inflammation. Results In the present study, we found that blocking TRPV4 diminishes LPS-induced cytosolic Ca2+-elevations, which are essential for glomerular endothelial inflammation and barrier function. Furthermore, TRPV4 regulated LPS-induced phosphorylation and translocation of NF-κB and IRF-3 in mouse glomerular endothelial cells (MRGEC). Clamping intracellular Ca2+ mimics the LPS-induce response seen in the absence of TRPV4. In vivo, pharmacological blockade or knock down of TRPV4 reduced the inflammatory response of glomerular endothelial cells, inhibited translocation of NF-κB and IRF-3, increased survival rate and improved renal function in CLP-induced sepsis but without altering renal cortical blood perfusion. Conclusions Taken together, these results suggested that inhibition of TRPV4 ameliorates glomerular endothelial inflammation, kidney dysfunction, and increased mortality via mediating Ca2+ overload and NF-κB/IRF-3 activation. These discoveries may provide novel pharmacological strategies for the treatment of glomerular endothelial dysfunction and kidney injury during endotoxemia, sepsis, and other inflammatory diseases.

Lactoferrin nanoparticles coencapsulated with curcumin and tenofovir improve vaginal defense against HIV-1 infection

Nanomedicine ◽  
2021 ◽  
Author(s):  
Samrajya Lakshmi Yeruva ◽  
Prashant Kumar ◽  
Seetharam Deepa ◽  
Anand K Kondapi
Keyword(s):  
Physicochemical Characterization ◽  
Systemic Circulation ◽  
Application Site ◽  
Drug Nanoparticles ◽  
In Vivo Experiments ◽  
Hiv Microbicide ◽  
Anti Hiv ◽  
Hiv 1

Aim: We report here the development of tenofovir- and curcumin-loaded lactoferrin nanoparticles (TCNPs) as an HIV-microbicide. Materials & methods: TCNPs were subjected to various physicochemical characterization experiments, followed by in vitro and in vivo experiments to assess their efficacy. Results: TCNPs had a diameter of 74.31 ± 2.56 nm with a gross encapsulation of more than 61% for each drug. Nanoparticles were effective against HIV-1 replication, with an IC50 of 1.75 μM for curcumin and 2.8 μM for tenofovir. TCNPs provided drug release at the application site for up to 8–12 h, with minimal leakage into the systemic circulation. TCNPs showed spermicidal activity at ≥200 μM and induced minimal cytotoxicity and inflammation in the vaginal epithelium as revealed by histopathological and ELISA studies. Conclusion: We demonstrated that TCNPs could serve as a novel anti-HIV microbicidal agent in rats. [Formula: see text]

scholarly journals α-Tocomonoenol Is Bioavailable in Mice and May Partly Be Regulated by the Function of the Hepatic α-Tocopherol Transfer Protein

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4803
Author(s):  
Andrea Irías-Mata ◽  
Nadine Sus ◽  
Maria-Lena Hug ◽  
Marco Müller ◽  
Walter Vetter ◽  
...  
Keyword(s):  
Tissue Distribution ◽  
Room Temperature ◽  
Systemic Circulation ◽  
Future Research ◽  
Wild Type ◽  
Transfer Protein ◽  
In Vivo Experiments ◽  
And Storage

Tocomonoenols are vitamin E derivatives present in foods with a single double bond at carbon 11’ in the sidechain. The α-tocopherol transfer protein (TTP) is required for the maintenance of normal α-tocopherol (αT) concentrations. Its role in the tissue distribution of α-11′-tocomonoenol (αT1) is unknown. We investigated the tissue distribution of αT1 and αT in wild-type (TTP+/+) and TTP knockout (TTP−/−) mice fed diets with either αT or αT1 for two weeks. αT1 was only found in blood, not tissues. αT concentrations in TTP+/+ mice were in the order of adipose tissue > brain > heart > spleen > lungs > kidneys > small intestine > liver. Loss of TTP function depleted αT in all tissues. αT1, contrary to αT, was still present in the blood of TTP−/− mice (16% of αT1 in TTP+/+). Autoclaving and storage at room temperature reduced αT and αT1 in experimental diets. In conclusion, αT1 is bioavailable, reaches the blood in mice, and may not entirely depend on TTP function for secretion into the systemic circulation. However, due to instability of the test compounds in the experimental diets, further in vivo experiments are required to clarify the role of TTP in αT1 secretion. Future research should consider compound stability during autoclaving of rodent feed.

scholarly journals The protective effect of klotho against contrast-associated acute kidney injury via the antioxidative effect

2019 ◽  
Vol 317 (4) ◽  
pp. F881-F889 ◽  
Author(s):  
Hyung Jung Oh ◽  
Hyewon Oh ◽  
Bo Young Nam ◽  
Je Sung You ◽  
Dong-Ryeol Ryu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Kidney Injury ◽  
Antioxidative Effect ◽  
In Vivo Experiments ◽  
Apoptotic Markers ◽  
Cytoplasmic Vacuoles ◽  
Transmission Electron ◽  
And Oxidative Stress

As oxidative stress is one major factor behind contrast-associated acute kidney injury (CA-AKI), we investigated the protective effect of klotho against CA-AKI via the antioxidative effect. In in vitro experiments, cells (NRK-52E) were divided into the following three groups: control, iopamidol, or iopamidol + recombinant klotho (rKL) groups. Moreover, cell viability was measured with the Cell Counting Kit-8 assay, and oxidative stress was examined with 2',7'-dichlorodihydrofluorescein diacetate fluorescence intensity. RT-PCR and Western blot analysis were performed to assess propidium iodide klotho expression, and Bax-to-Bcl-2 and apoptosis ratios were evaluated with annexin V/Hoechst 33342 staining. Furthermore, we knocked down the klotho gene using siRNA to verify the endogenous effect of klotho. In our in vivo experiments, oxidative stress was evaluated with the thiobarbituric acid-reactive substance assay, and apoptosis was evaluated with the Bax-to-Bcl-2 ratio and cleaved caspase-3 immunohistochemistry. Additionally, cell and tissue morphology were investigated with transmission electron microscopy. In both in vitro and in vivo experiments, mRNA and protein expression of klotho significantly decreased in CA-AKI mice compared with control mice, whereas oxidative stress and apoptosis markers were significantly increased in CA-AKI mice. However, rKL supplementation mitigated the elevated apoptotic markers and oxidative stress in the CA-AKI mouse model and improved cell viability. In contrast, oxidative stress and apoptotic markers were more aggravated when the klotho gene was knocked down. Moreover, we found more cytoplasmic vacuoles in the CA-AKI mouse model using transmission electron microscopy but fewer cytoplasmic vacuoles in rKL-supplemented cells. The present study shows that klotho in proximal tubular cells can protect against CA-AKI via an antioxidative effect.

Dexamethasone-Induced Increase in Lymphocyte β-Adrenergic Receptor Density and cAMP Formation in vivo

Pharmacology ◽  
2002 ◽  
Vol 67 (1) ◽  
pp. 1-5 ◽  
Author(s):  
G. Abraham ◽  
G.F. Schusser ◽  
F.R. Ungemach
Keyword(s):  
Adrenergic Receptor ◽  
Receptor Density ◽  
Camp Formation

Response of C-6 glioma to isoproterenol and papaverine in vivo depends on ?-adrenergic receptor density

1984 ◽  
Vol 15 (1) ◽  
pp. 96-99 ◽  
Author(s):  
Ewa Chelmicka-Schorr ◽  
Michael G. Sportiello ◽  
Samir F. Atweh ◽  
Barry G. W. Arnason
Keyword(s):  
Adrenergic Receptor ◽  
Receptor Density

scholarly journals Maternal separation diminishes α-adrenergic receptor density and function in renal vasculature from male Wistar-Kyoto rats

2017 ◽  
Vol 313 (1) ◽  
pp. F47-F54 ◽  
Author(s):  
Analia S. Loria ◽  
Jeffrey L. Osborn
Keyword(s):  
Adrenergic Receptor ◽  
Baroreflex Sensitivity ◽  
Maternal Separation ◽  
Receptor Expression ◽  
Male Rats ◽  
Receptor Density ◽  
Renal Vasculature ◽  
And Function ◽  
Renal Vascular ◽  
And Control

Adult rats exposed to maternal separation (MatSep) are normotensive but display lower glomerular filtration rate and increased renal neuroadrenergic drive. The aim of this study was to determine the renal α-adrenergic receptor density and the renal vascular responsiveness to adrenergic stimulation in male rats exposed to MatSep. In addition, baroreflex sensitivity was assessed to determine a component of neural control of the vasculature. Using tissue collected from 4-mo-old MatSep and control rats, α1-adrenergic receptors (α1-ARs) were measured in renal cortex and isolated renal vasculature using receptor binding assay, and the α-AR subtype gene expression was determined by RT-PCR. Renal cortical α1-AR density was similar between MatSep and control tissues (Bmax = 44 ± 1 vs. 42 ± 2 fmol/mg protein, respectively); however, MatSep reduced α1-AR density in renal vasculature (Bmax = 47 ± 4 vs. 62 ± 4 fmol/mg protein, P < 0.05, respectively). In a separate group of rats, the pressor, bradycardic, and renal vascular constrictor responses to acute norepinephrine injection (NE, 0.03–0.25 μg/μl) were determined under anesthesia. Attenuated NE-induced renal vasoconstriction was observed in rats exposed to MatSep compared with control ( P < 0.05). A third group of rats was infused at steady state with the α1 agonist phenylephrine (10 μg/min iv) and vasodilator sodium nitroprusside (5 μg/min iv). The difference between the change in heart rate/mean arterial pressure slopes was indicative of reduced baroreflex sensitivity in MatSep vs. control rats (−0.45 ± 0.04 vs. −0.95 ± 0.07 beats·min−1·mmHg−1, P < 0.05). These data support the notion that reduced α-adrenergic receptor expression and function in the renal vasculature could develop secondary to MatSep-induced overactivation of the renal neuroadrenergic tone.

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