Prkdc participates in mitochondrial genome maintenance and prevents Adriamycin-induced nephropathy in mice.
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ABSTRACT:
SUBMITTER: Papeta N
PROVIDER: S-EPMC2964992 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Human induced pluripotent stem cell-derived mesenchymal stem cells (iPS-MSCs) are emerging as attractive options for use in cell replacement therapy, but their effect in kidney diseases remains unknown. Here, we showed that intravenous injection of iPS-MSCs protect against renal function loss in both short-term and long-term models of adriamycin nephropathy (AN). In the short-term AN model, iPS-MSCs conferred a substantial anti-apoptotic effect on tubular cells, associated with a downregulation of Bax and Bax/Bcl2 ratio and an upregulation of survivin expression. In vitro, conditioned medium from iPS-MSCs (iPSMSC-CM) significantly limited albumin-induced tubular apoptosis and enhanced tubular proliferation, accompanied by a reduced expression of tubular Bax and an elevated expression of Bcl2 and survivin. Oxidative stress was markedly attenuated by iPS-MSCs both in AN mice and in protein-overloaded tubular cells. In the long-term AN model, repeated injections of iPS-MSCs significantly inhibited tubulointerstitial fibrosis and reduced intrarenal deposition of collagen I, collagen IV and ?SMA. Modulation of the hedgehog signaling pathway contributed to the anti-fibrotic effect of iPS-MSCs in chronic AN. Finally, we detected that most of the infused iPS-MSCs were entrapped in the lungs. In conclusion, our data support a beneficial role of iPS-MSCs in both acute and chronic AN.
| S-EPMC5732756 | biostudies-literature
Project description:The aim of this study is to evaluate the effects of pravastatin on Adriamycin (ADR)-induced nephropathy and the mechanisms involved. Forty rats were divided into the following 4 groups: control, ADR (15 mg.kg-1, IP), ADR plus pravastatin (20 mg.kg-1 which was started 5 days prior to ADR injection), and ADR plus pravastatin (20 mg.kg-1 which was started 5 days after ADR injection). On day 20 after ADR injection, the animals were sacrificed. The results showed that administration of pravastatin decreased the levels of 24-h urinary protein (24-h UP), blood urea nitrogen (BUN), and creatinine (p < 0.05) which had increased after the injection of ADR; in addition, pravastatin reversed structural changes seen in ADR group. Furthermore, pravastatin elevated mRNA and protein expression of nephrin (p < 0.05) which had been reduced in ADR group. We conclude that pravastatin protects and treats renal injury induced by ADR.
| S-EPMC6269566 | biostudies-literature
Project description:Adriamycin, a widely used anthracycline antibiotic in multiple chemotherapy regimens, has been challenged by the cardiotoxicity leading to fatal congestive heart failure in the worst condition. The present study demonstrated that Dihydromyricetin, a natural product extracted from ampelopsis grossedentat, exerted cardioprotective effect against the injury in Adriamycin-administrated ICR mice. Dihydromyricetin decreased ALT, LDH and CKMB levels in mice serum, causing a significant reduction in the toxic death triggered by Adriamycin. The protective effects were also indicated by the alleviation of abnormal electrocardiographic changes, the abrogation of proliferation arrest and apoptotic cell death in primary myocardial cells. Further study revealed that Dihydromyricetin-rescued loss of anti-apoptosis protein ARC provoked by Adriamycin was involved in the cardioprotection. Intriguingly, the anticancer activity of Adriamycin was not compromised upon the combination with Dihydromyricetin, as demonstrated by the enhanced anticancer effect achieved by Adriamycin plus Dihydromyricetin in human leukemia U937 cells and xenograft models, in a p53-dependent manner. These results collectively promised the potential value of Dihydromyricetin as a rational cardioprotective agent of Adriamycin, by protecting myocardial cells from apoptosis, while potentiating anticancer activities of Adriamycin, thus further increasing the therapeutic window of the latter one.
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Project description:Maximising the use of preclinical murine models of progressive kidney disease as test beds for therapies ideally requires kidney function to be measured repeatedly in a safe, minimally invasive manner. To date, most studies of murine nephropathy depend on unreliable markers of renal physiological function, exemplified by measuring blood levels of creatinine and urea, and on various end points necessitating sacrifice of experimental animals to assess histological damage, thus counteracting the principles of Replacement, Refinement and Reduction. Here, we applied two novel minimally invasive techniques to measure kidney function in SCID mice with adriamycin-induced nephropathy. We employed i) a transcutaneous device that measures the half-life of intravenously administered FITC-sinistrin, a molecule cleared by glomerular filtration; and ii) multispectral optoacoustic tomography, a photoacoustic imaging device that directly visualises the clearance of the near infrared dye, IRDye 800CW carboxylate. Measurements with either technique showed a significant impairment of renal function in experimental animals versus controls, with significant correlations with the proportion of scarred glomeruli five weeks after induction of injury. These technologies provide clinically relevant functional data and should be widely adopted for testing the efficacies of novel therapies. Moreover, their use will also lead to a reduction in experimental animal numbers.
| S-EPMC4556979 | biostudies-literature
Project description:BackgroundCatalase is an important antioxidant enzyme that regulates the level of intracellular hydrogen peroxide and hydroxyl radicals. The effects of catalase deficiency on albuminuria and progressive glomerulosclerosis have not yet been fully elucidated. The adriamycin (ADR) nephropathy model is considered to be an experimental model of focal segmental glomerulosclerosis. A functional catalase deficiency was hypothesized to exacerbate albuminuria and the progression of glomerulosclerosis in this model.MethodsADR was intravenously administered to both homozygous acatalasemic mutant mice (C3H/AnLCs(b)Cs(b)) and control wild-type mice (C3H/AnLCs(a)Cs(a)). The functional and morphological alterations of the kidneys, including albuminuria, renal function, podocytic, glomerular and tubulointerstitial injuries, and the activities of catalase were then compared between the two groups up to 8 weeks after disease induction. Moreover, the presence of a mutation of the toll-like receptor 4 (tlr4) gene, which was previously reported in the C3H/HeJ strain, was investigated in both groups.ResultsThe ADR-treated mice developed significant albuminuria and glomerulosclerosis, and the degree of these conditions in the ADR-treated acatalasemic mice was higher than that in the wild-type mice. ADR induced progressive renal fibrosis, renal atrophy and lipid peroxide accumulation only in the acatalasemic mice. In addition, the level of catalase activity was significantly lower in the kidneys of the acatalasemic mice than in the wild-type mice during the experimental period. The catalase activity increased after ADR injection in wild-type mice, but the acatalasemic mice did not have the ability to increase their catalase activity under oxidative stress. The C3H/AnL strain was found to be negative for the tlr4 gene mutation.ConclusionsThese data indicate that catalase deficiency plays an important role in the progression of renal injury in the ADR nephropathy model.
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Project description:Minimal change disease (MCD) is the most common cause of idiopathic nephrotic syndrome in children. The current major therapy is hormones for most steroid-sensitive patients. However, many patients have recurrent relapses of the disease and require long-term immunosuppression, leading to significant morbidity due to the side effects of the drugs. Therefore, better drugs need to be urgently explored to treat nephrotic syndrome while avoiding the side effects of drugs. Minnelide, a water-soluble prodrug of triptolide, has been proved to be effective in treating cancers in many clinical trials. This study aimed to investigate the therapeutic effect of minnelide in mice with adriamycin (ADR) nephropathy, its underlying protection mechanisms, and its reproductive toxicity. Minnelide was administered intraperitoneally to 6-8-week female mice with adriamycin nephropathy for 2 weeks, and the urine, blood, and kidney tissues were taken to analyze the therapeutic effect. In addition, we evaluated reproductive toxicity by measuring the levels of gonadal hormones and observing the histological changes in ovaries and testes. Primary mouse podocytes were exposed to puromycin (PAN) to damage the cytoskeleton and induce apoptosis, and then, triptolide was used to evaluate the therapeutic effect and underlying protection mechanisms in vitro. It was observed that minnelide dramatically alleviated proteinuria and apoptosis in mice with adriamycin nephropathy. In vitro, triptolide ameliorated puromycin-induced cytoskeletal rearrangement and apoptosis via reactive oxygen species-mediated mitochondrial pathway. In addition, minnelide caused no reproductive toxicity to male and female mice. The results suggested that minnelide might be a promising drug for nephrotic syndrome.
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Project description:Reactive oxygen species (ROS), which excessively arise in diabetes and systemic inflammatory diseases, modify cellular lipids and cellular lipid composition leading to altered biophysical properties of cellular membranes. The impact of lipid peroxidation on transmembrane signaling routes is not yet well studied. The canonical transient receptor potential channel 6 (TRPC6) is implicated in the pathogenesis of several forms of glomerular diseases. TRPC6 is sensitive to membrane stretch and relies on a distinct lipid environment. This study investigates the effect of oxidative alterations to plasma membrane lipids on TRPC6 activity and the function of the glomerular filter. Knockout of the anti-oxidative, lipid modifying enzyme paraoxonase 2 (PON2) leads to altered biophysical properties of glomerular epithelial cells, which are called podocytes. Cortical stiffness, quantified by atomic force microscopy, was largely increased in PON2-deficient cultured podocytes. PON2 deficiency markedly enhanced TRPC6 channel currents and channel recovery. Treatment with the amphiphilic substance capsazepine in micromolar doses reduced cortical stiffness and abrogated TRPC6 conductance. In in vivo studies, capsazepine reduced the glomerular phenotype in the model of adriamycin-induced nephropathy in PON2 knockout mice and wildtype littermates. In diabetic AKITA mice, the progression of albuminuria and diabetic kidney disease was delayed. In summary, we provide evidence that the modification of membrane characteristics affects TRPC6 signaling. These results could spur future research to investigate modification of the direct lipid environment of TRPC6 as a future therapeutic strategy in glomerular disease.
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Project description:Inflammation has recently been attributed to dysbiosis of the gut microbiome, which has been linked to proteinuria in chronic kidney disease. Since Adriamycin® (ADR) is widely used to induce proteinuria in mouse models, the aim of this study was to explore the potential effect of gut microbiome on this process. Both ADR resistant (C57BL/6) and susceptible (BALB/C) strains were part of the induced nephropathy with ADR injection. BALB/C mice significantly presented increased urinary albumin/creatinine ratio (UACR) with renal lesions in pathology, but C57BL/6 mice were absent from kidney damage. Species and genus level resolution analysis showed a shift in gut microbial profile between BALB/C and C57BL/6 mice. ADR further altered the stool microbiome in BALB/C mice, particularly with enrichment of Odoribacter and depletion of Turicibacter, Marvinbryantia and Rikenella. Moreover, the level of UACR in BALB/C mice was marked related to the abundance of Marvinbryantia, Odoribacter and Turicibacter in stool. Meanwhile, ADR remarkably increased the serum levels of interleukin (IL)-2 in BALB/C mice, but not in C57BL/6 mice. It is suggested that the favorably altered stools as shown in the microbiome might promote the inflammation and proteinuria in ADR-sensitive mice, which provides a new insight on the pathogenicity of chronic kidney disease.
| S-EPMC5833890 | biostudies-literature
Project description:BackgroundsKlotho protein interacts with the transforming growth factor ? (TGF-?) receptor and Wnt, which contribute to the progression of renal disease, inhibiting their signals. Renal and circulating klotho levels are diminished in chronic kidney disease.MethodsExperiments were performed to assess whether supplementation of klotho protein could have protective effects on the kidney. Rats were injected with adriamycin (5 mg/kg) and divided into three groups: those treated with vehicle, those treated with klotho protein and those treated with klotho plus 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD). Rats without adriamycin treatment were used as a control.ResultsAdriamycin reduced the serum klotho concentration and renal expression of klotho and E-cadherin. Adriamycin also increased the renal expression of Wnt, TGF-?, and angiotensinogen, as well as the renal abundance of ?-catenin and angiotensin II. Klotho supplementation suppressed adriamycin-induced elevations of ?-catenin and angiotensin II with sustained Wnt expression. Combined treatment with klotho and TDZD reversed the klotho-induced improvements in the renal abundance of ?-catenin and angiotensin II as well as the expression of TGF-? and angiotensinogen without affecting E-cadherin.ConclusionsOur data indicate that Wnt is involved in the pathogenesis of adriamycin nephropathy. Furthermore, klotho supplementation inhibited Wnt signaling, ameliorating renal angiotensin II. Finally, klotho protein appears to suppress epithelial-mesenchymal transition by inhibiting TGF-? and Wnt signaling.
| S-EPMC6251653 | biostudies-literature
Project description:Objective:This study is aimed at investigating the efficacy of CTLA4-Ig abatacept in normalizing proteinuria and its possible mechanism in adriamycin-induced nephropathy (AIN) rats. Methods:A total of 32 healthy male Sprague-Dawley rats were randomly divided into a normal group, an AIN group, an abatacept group, and a prednisone group. Adriamycin (6.5?mg/kg) was injected once via the tail vein of rats to induce nephrotic syndrome. After adriamycin treatment, the abatacept group rats were given abatacept (0.5?mg/kg) once by intraperitoneal injection on day 14. In addition, the prednisone group rats were given prednisone (12.5?mg/kg) daily consecutively by gavage from day 14 to day 21. Blood, urine, and kidney tissue specimens were collected when sacrificed on day 21. The 24-hour urinary protein, serum albumin, cholesterol, creatinine, and urea nitrogen were then detected. An enzyme-linked immunosorbent assay was used to determine the level of urine CD80 and serum IL-17. Flow cytometry was used to investigate the prevalence of circulating Treg. Hematoxylin-eosin staining and electron microscopy were used for a renal histological study. Immunofluorescence staining was performed to confirm the CD80 expression of renal tissue. Results:The 24-hour urinary protein of the abatacept group was significantly lower than that of the prednisone group and the AIN group. The level of urine CD80 of the abatacept group was significantly lower than that of the AIN group. Compared with the AIN group and the prednisone group, the circulating Treg prevalence of the abatacept group was significantly higher, while the level of serum IL-17 was lower. A negative kidney staining of CD80 expression was demonstrated in each group in this study. The 24-hour urinary protein had a negative correlation with the circulating Treg prevalence and Treg/IL-17 and a positive correlation with the urine CD80 and serum IL-17. Urinary CD80 had a positive correlation with serum IL-17 and no correlation with the circulating Treg prevalence. Conclusions:CTLA4-Ig abatacept can reduce proteinuria of adriamycin-induced nephropathy rats, possibly at least partially as a result of regulating circulating Treg/IL-17. CTLA4-Ig abatacept could be a promising regimen for idiopathic nephrotic syndrome.
| S-EPMC7201454 | biostudies-literature