scholarly journals Klotho deficiency intensifies hypoxia-induced expression of IFN-α/β through upregulation of RIG-I in kidneys

PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258856
Author(s):  
Asako Urabe ◽  
Shigehiro Doi ◽  
Ayumu Nakashima ◽  
Takeshi Ike ◽  
Kenichi Morii ◽  
...  
Keyword(s):  
Iga Nephropathy ◽  
Rat Kidney ◽  
Human Kidney ◽  
Induced Expression ◽  
Expression Levels ◽  
Hypoxic Conditions ◽  
Normal Rat ◽  
End Stage

Hypoxia is a common pathway to the progression of end-stage kidney disease. Retinoic acid-inducible gene I (RIG-I) encodes an RNA helicase that recognizes viruses including SARS-CoV2, which is responsible for the production of interferon (IFN)-α/β to prevent the spread of viral infection. Recently, RIG-I activation was found under hypoxic conditions, and klotho deficiency was shown to intensify the activation of RIG-I in mouse brains. However, the roles of these functions in renal inflammation remain elusive. Here, for in vitro study, the expression of RIG-I and IFN-α/β was examined in normal rat kidney (NRK)-52E cells incubated under hypoxic conditions (1% O2). Next, siRNA targeting RIG-I or scramble siRNA was transfected into NRK52E cells to examine the expression of RIG-I and IFN-α/β under hypoxic conditions. We also investigated the expression levels of RIG-I and IFN-α/β in 33 human kidney biopsy samples diagnosed with IgA nephropathy. For in vivo study, we induced renal hypoxia by clamping the renal artery for 10 min in wild-type mice (WT mice) and Klotho-knockout mice (Kl−/− mice). Incubation under hypoxic conditions increased the expression of RIG-I and IFN-α/β in NRK52E cells. Their upregulation was inhibited in NRK52E cells transfected with siRNA targeting RIG-I. In patients with IgA nephropathy, immunohistochemical staining of renal biopsy samples revealed that the expression of RIG-I was correlated with that of IFN-α/β (r = 0.57, P<0.001, and r = 0.81, P<0.001, respectively). The expression levels of RIG-I and IFN-α/β were upregulated in kidneys of hypoxic WT mice and further upregulation was observed in hypoxic Kl−/− mice. These findings suggest that hypoxia induces the expression of IFN-α/β through the upregulation of RIG-I, and that klotho deficiency intensifies this hypoxia-induced expression in kidneys.

scholarly journals 3′-Untranslated regions of oxidative phosphorylation mRNAs function in vivo as enhancers of translation

2000 ◽  
Vol 352 (1) ◽  
pp. 109-115 ◽  
Author(s):  
Carlo M. Di LIEGRO ◽  
Marianna BELLAFIORE ◽  
José M. IZQUIERDO ◽  
Anja RANTANEN ◽  
José M. CUEZVA
Keyword(s):  
Oxidative Phosphorylation ◽  
Atp Synthase ◽  
Fluorescent Protein ◽  
Rat Kidney ◽  
In Vitro Translation ◽  
Mitochondrial Transcription Factor ◽  
Normal Rat ◽  
Green Fluorescent

Recent findings have indicated that the 3´-untranslated region (3´-UTR) of the mRNA encoding the β-catalytic subunit of the mitochondrial H+-ATP synthase has an in vitro translation-enhancing activity (TEA) [Izquierdo and Cuezva, Mol. Cell. Biol. (1997) 17, 5255–5268; Izquierdo and Cuezva, Biochem. J. (2000) 346, 849–855]. In the present work, we have expressed chimaeric plasmids that encode mRNA variants of green fluorescent protein in normal rat kidney and liver clone 9 cells to determine whether the 3´-UTRs of nuclear-encoded mRNAs involved in the biogenesis of mitochondria have an intrinsic TEA. TEA is found in the 3´-UTR of the mRNAs encoding the α- and β-subunits of the rat H+-ATP synthase complex, as well as in subunit IV of cytochrome c oxidase. No TEA is present in the 3´-UTR of the somatic mRNA encoding rat mitochondrial transcription factor A. Interestingly, the TEA of the 3´-UTR of mRNAs of oxidative phosphorylation is different, depending upon the cell type analysed. These data provide the first in vivo evidence of a novel cell-specific mechanism for the control of the translation of mRNAs required in mitochondrial function.

scholarly journals COMPARISON OF REACTIONS OF ANTIBODIES TO RAT COLLAGEN AND TO RAT KIDNEY IN THE BASEMENT MEMBRANES OF RAT RENAL GLOMERULI

1969 ◽  
Vol 129 (6) ◽  
pp. 1145-1161 ◽  
Author(s):  
Sidney Rothbard ◽  
Robert F. Watson
Keyword(s):  
Rat Kidney ◽  
Basement Membranes ◽  
Heterologous Antigen ◽  
In Vitro Methods ◽  
Homologous Antigen ◽  
Normal Rat ◽  
Immunofluorescence Antibody ◽  
Glomerular Capillaries

By in vivo and in vitro methods of immunofluorescence, antibody to rat collagen and to rat kidney show the same regular, linear fluorescence following the outlines of the renal glomerular capillaries. Absorption of each antiserum with its homologous antigen completely removed the antibody for immunofluorescence, while absorption with the heterologous antigen had no effect. The nephrotoxicity persisted in the anti-kidney serum absorbed with collagen. By pretreatment of frozen normal rat kidney sections with various enzymes followed by immunofluorescence, it was shown that trypsin and hyaluronidase had no effect on the subsequent fluorescence of either antibody; papain reduced the fluorescence; and pepsin and Pronase acted on both antigens so that no fluorescence was present. One preparation of neuraminidase, derived from V. cholerae, reduced fluorescence of both antibodies in some preparations, but the same enzyme derived from influenza virus or C. perfringens had no effect on either. Collagenase completely prevented fluorescence of the antibody to collagen and had no effect on that to rat kidney. The findings in this study show that the antibody to collagen is directed to collagen in rat renal glomerular basement membranes and that the antibody to rat kidney reacts with some antigen other than collagen in these membranes.

scholarly journals Bioprinting of kidney in vitro models: cells, biomaterials, and manufacturing techniques

2021 ◽  
Author(s):  
Maaike F.J. Fransen ◽  
Gabriele Addario ◽  
Carlijn V.C. Bouten ◽  
Franck Halary ◽  
Lorenzo Moroni ◽  
...  
Keyword(s):  
Renal Disease ◽  
Human Kidney ◽  
In Vitro Models ◽  
Renal Cells ◽  
Number Of Patients ◽  
Manufacturing Techniques ◽  
Stage Renal Disease ◽  
End Stage

Abstract The number of patients with end-stage renal disease is continuously increasing worldwide. The only therapies for these patients are dialysis and organ transplantation, but the latter is limited due to the insufficient number of donor kidneys available. Research in kidney disease and alternative therapies are therefore of outmost importance. In vitro models that mimic human kidney functions are essential to provide better insights in disease and ultimately novel therapies. Bioprinting techniques have been increasingly used to create models with some degree of function, but their true potential is yet to be achieved. Bioprinted renal tissues and kidney-like constructs presents challenges, for example, choosing suitable renal cells and biomaterials for the formulation of bioinks. In addition, the fabrication of complex renal biological structures is still a major bottleneck. Advances in pluripotent stem cell-derived renal progenitors has contributed to in vivo-like rudiment structures with multiple renal cells, and these started to make a great impact on the achieved models. Natural- or synthetic-based biomaterial inks, such as kidney-derived extracellular matrix and gelatin-fibrin hydrogels, which show the potential to partially replicate in vivo-like microenvironments, have been largely investigated for bioprinting. As the field progresses, technological, biological and biomaterial developments will be required to yield fully functional in vitro tissues that can contribute to a better understanding of renal disease, to improve predictability in vitro of novel therapeutics, and to facilitate the development of alternative regenerative or replacement treatments. In this review, we resume the main advances on kidney in vitro models reported so far.

Effect of UUO on D1aR expression reveals a link among dopamine, transforming growth factor-β, and nitric oxide

2004 ◽  
Vol 286 (3) ◽  
pp. F509-F515 ◽  
Author(s):  
Joshua M. Stern ◽  
Jie Chen ◽  
Randi B. Silver ◽  
Dix P. Poppas ◽  
E. Darracott Vaughan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Rat Kidney ◽  
Transforming Growth Factor Β ◽  
Kidney Tubules ◽  
Concurrent Treatment ◽  
Normal Rat

Interactions between transforming growth factor-β (TGF-β) and nitric oxide (NO) are important in the pathophysiology of unilateral ureteral obstruction (UUO). Dopamine (DA) is a vasoactive renal mediator active at the D1A receptor (D1AR), which has not been studied in UUO; therefore, we examined the interactions among DA, TGF-β, and NO in UUO. In vivo, UUO was carried out in rats with or without concurrent treatment with 1D11, a monoclonal antibody to TGF-β, for 14 days. In vitro, NRK-52E cells (normal rat kidney tubules) were treated with DA, and NO and TGF-β release were examined. UUO resulted in a 70% decrease in the expression of renal D1AR, confirmed by both Western blot analysis and immunohistochemistry. 1D11 treatment restored expression to 60% of control values. DA treatment decreased NRK-52E release of TGF-β by 80%; conversely, DA significantly increased NO release from NRK-52E cells. These results suggest that DA modulates the release of cytokines, which are involved in the fibrotic and apoptotic sequelae of UUO, and that these effects are independent of DA's known vasoactive properties.

Evidence for an Increased Generation of Prostacyclin in the Microvasculature and an Impairment of the Platelet α-Granule Release in Chronic Renal Failure

1988 ◽  
Vol 60 (02) ◽  
pp. 205-208 ◽  
Author(s):  
Paul A Kyrle ◽  
Felix Stockenhuber ◽  
Brigitte Brenner ◽  
Heinz Gössinger ◽  
Christian Korninger ◽  
...  
Keyword(s):  
Renal Failure ◽  
Chronic Renal Failure ◽  
Blood Clotting ◽  
Normal Subjects ◽  
Chronic Uraemia ◽  
Wall Interaction ◽  
End Stage ◽  
Granule Release

SummaryThe formation of prostacyclin (PGI2) and thromboxane A2 and the release of beta-thromboglobulin (beta-TG) at the site of platelet-vessel wall interaction, i.e. in blood emerging from a standardized injury of the micro vasculature made to determine bleeding time, was studied in patients with end-stage chronic renal failure undergoing regular haemodialysis and in normal subjects. In the uraemic patients, levels of 6-keto-prostaglandin F1α (6-keto-PGF1α) were 1.3-fold to 6.3-fold higher than the corresponding values in the control subjects indicating an increased PGI2 formation in chronic uraemia. Formation of thromboxane B2 (TxB2) at the site of plug formation in vivo and during whole blood clotting in vitro was similar in the uraemic subjects and in the normals excluding a major defect in platelet prostaglandin metabolism in chronic renal failure. Significantly smaller amounts of beta-TG were found in blood obtained from the site of vascular injury as well as after in vitro blood clotting in patients with chronic renal failure indicating an impairment of the a-granule release in chronic uraemia. We therefore conclude that the haemorrhagic diathesis commonly seen in patients with chronic renal failure is - at least partially - due to an acquired defect of the platelet a-granule release and an increased generation of PGI2 in the micro vasculature.

scholarly journals Survival and Proliferation under Severely Hypoxic Microenvironments Using Cell-Laden Oxygenating Hydrogels

2021 ◽  
Vol 12 (2) ◽  
pp. 30
Author(s):  
Shabir Hassan ◽  
Berivan Cecen ◽  
Ramon Peña-Garcia ◽  
Fernanda Roberta Marciano ◽  
Amir K. Miri ◽  
...  
Keyword(s):  
Prolonged Release ◽  
Therapeutic Approaches ◽  
Encapsulated Cells ◽  
Hypoxic Conditions ◽  
Skeletal Myoblasts ◽  
Artificial Tissue ◽  
Delivery Platform ◽  
Living Tissues

Different strategies have been employed to provide adequate nutrients for engineered living tissues. These have mainly revolved around providing oxygen to alleviate the effects of chronic hypoxia or anoxia that result in necrosis or weak neovascularization, leading to failure of artificial tissue implants and hence poor clinical outcome. While different biomaterials have been used as oxygen generators for in vitro as well as in vivo applications, certain problems have hampered their wide application. Among these are the generation and the rate at which oxygen is produced together with the production of the reaction intermediates in the form of reactive oxygen species (ROS). Both these factors can be detrimental for cell survival and can severely affect the outcome of such studies. Here we present calcium peroxide (CPO) encapsulated in polycaprolactone as oxygen releasing microparticles (OMPs). While CPO releases oxygen upon hydrolysis, PCL encapsulation ensures that hydrolysis takes place slowly, thereby sustaining prolonged release of oxygen without the stress the bulk release can endow on the encapsulated cells. We used gelatin methacryloyl (GelMA) hydrogels containing these OMPs to stimulate survival and proliferation of encapsulated skeletal myoblasts and optimized the OMP concentration for sustained oxygen delivery over more than a week. The oxygen releasing and delivery platform described in this study opens up opportunities for cell-based therapeutic approaches to treat diseases resulting from ischemic conditions and enhance survival of implants under severe hypoxic conditions for successful clinical translation.

scholarly journals A therapeutic vascular conduit to support in vivo cell-secreted therapy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Edward X. Han ◽  
Hong Qian ◽  
Bo Jiang ◽  
Maria Figetakis ◽  
Natalia Kosyakova ◽  
...  
Keyword(s):  
Vascular Graft ◽  
Large Scale ◽  
Biological Effects ◽  
Therapeutic Protein ◽  
Close Proximity ◽  
Delivery Platform ◽  
Stage Renal Disease ◽  
End Stage

AbstractA significant barrier to implementation of cell-based therapies is providing adequate vascularization to provide oxygen and nutrients. Here we describe an approach for cell transplantation termed the Therapeutic Vascular Conduit (TVC), which uses an acellular vessel as a scaffold for a hydrogel sheath containing cells designed to secrete a therapeutic protein. The TVC can be directly anastomosed as a vascular graft. Modeling supports the concept that the TVC allows oxygenated blood to flow in close proximity to the transplanted cells to prevent hypoxia. As a proof-of-principle study, we used erythropoietin (EPO) as a model therapeutic protein. If implanted as an arteriovenous vascular graft, such a construct could serve a dual role as an EPO delivery platform and hemodialysis access for patients with end-stage renal disease. When implanted into nude rats, TVCs containing EPO-secreting fibroblasts were able to increase serum EPO and hemoglobin levels for up to 4 weeks. However, constitutive EPO expression resulted in macrophage infiltration and luminal obstruction of the TVC, thus limiting longer-term efficacy. Follow-up in vitro studies support the hypothesis that EPO also functions to recruit macrophages. The TVC is a promising approach to cell-based therapeutic delivery that has the potential to overcome the oxygenation barrier to large-scale cellular implantation and could thus be used for a myriad of clinical disorders. However, a complete understanding of the biological effects of the selected therapeutic is absolutely essential.

scholarly journals Uremic Toxins and Their Relation with Oxidative Stress Induced in Patients with CKD

2021 ◽  
Vol 22 (12) ◽  
pp. 6196
Author(s):  
Anna Pieniazek ◽  
Joanna Bernasinska-Slomczewska ◽  
Lukasz Gwozdzinski
Keyword(s):  
Oxidative Stress ◽  
Uremic Toxins ◽  
Water Medium ◽  
Induce Insulin Resistance ◽  
Risk Of Mortality ◽  
Increased Risk ◽  
Stage Renal Disease ◽  
End Stage

The presence of toxins is believed to be a major factor in the development of uremia in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Uremic toxins have been divided into 3 groups: small substances dissolved in water, medium molecules: peptides and low molecular weight proteins, and protein-bound toxins. One of the earliest known toxins is urea, the concentration of which was considered negligible in CKD patients. However, subsequent studies have shown that it can lead to increased production of reactive oxygen species (ROS), and induce insulin resistance in vitro and in vivo, as well as cause carbamylation of proteins, peptides, and amino acids. Other uremic toxins and their participation in the damage caused by oxidative stress to biological material are also presented. Macromolecules and molecules modified as a result of carbamylation, oxidative stress, and their adducts with uremic toxins, may lead to cardiovascular diseases, and increased risk of mortality in patients with CKD.

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