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1.
Sheng Li Xue Bao ; 72(5): 660-666, 2020 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-33106836

RESUMO

Under the hypoxic condition, organs or cells trigger a series of reactions or responses to adapt to the physiological requirement. These responses involve a complex regulation at different levels from organs, in particular the kidney (producing erythropoietin), to cells throughout the body. Actually, the responses to hypoxia from adaption to injury largely depend on the degree and time of hypoxia. In the past two decades, with the discovery of hypoxia-inducible factor (HIF), the mechanisms of erythropoiesis regulation were elucidated gradually, which has provided a novel therapeutic strategy for hypoxia-related diseases, especially renal anemia. In this review we focus on the latest advances in oxygen sensing and adaptive mechanism.


Assuntos
Anemia , Nefropatias , Humanos , Hipóxia , Rim , Oxigênio
2.
Ren Fail ; 42(1): 912-925, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32869703

RESUMO

Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) are orally active first-in-class new generation drugs for renal anemia. This extensive meta-analysis of randomized controlled trials (RCTs) was designed to provide clear information on the efficacy and safety of HIF-PHIs on anemia in chronic kidney disease (CKD) patients. Searches included PubMed, Web of Science, Ovid MEDLINE, and Cochrane Library database up to October 2019. RCTs of patients with CKD comparing HIF-PHIs with erythropoiesis-stimulating agents (ESAs) or placebo in the treatment of anemia. The primary outcome was hemoglobin change from baseline (Hb CFB); the secondary outcomes included iron-related parameters and the occurrence of each adverse event. 26 trials in 17 articles were included, with a total of 2804 dialysis or patients with CKD. HIF-PHIs treatment produced a significant beneficial effect on Hb CFB compared with the placebo group (MD, 0.69; 95% CI, 0.36 to 1.02). However, this favored effect of HIF-PHIs treatment was not observed in subgroup analysis among trials compared with ESAs (MD, 0.06; 95% CI, -0.20 to 0.31). The significant reduction in hepcidin by HIF-PHIs was observed in all subgroups when compared with the placebo group, whereas this effect was observed only in NDD-CKD patients when compared with ESAs. HIF-PHIs increased the risk of nausea (RR, 2.20; 95% CI, 1.06 to 4.53) and diarrhea (RR, 1.75; 95% CI, 1.06 to 2.92). We conclude that orally given HIF-PHIs are at least as efficacious as ESAs treatment to correct anemia short term in patients with CKD. In addition, HIF-PHIs improved iron metabolism and utilization in patients with CKD.

3.
Sci Adv ; 6(33): eaaz0748, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32851154

RESUMO

Recently, extracellular vesicles (EVs) have been attracting strong research interest for use as natural drug delivery systems. We report an approach to manufacturing interleukin-10 (IL-10)-loaded EVs (IL-10+ EVs) by engineering macrophages for treating ischemic acute kidney injury (AKI). Delivery of IL-10 via EVs enhanced not only the stability of IL-10, but also its targeting to the kidney due to the adhesive components on the EV surface. Treatment with IL-10+ EVs significantly ameliorated renal tubular injury and inflammation caused by ischemia/reperfusion injury, and potently prevented the transition to chronic kidney disease. Mechanistically, IL-10+ EVs targeted tubular epithelial cells, and suppressed mammalian target of rapamycin signaling, thereby promoting mitophagy to maintain mitochondrial fitness. Moreover, IL-10+ EVs efficiently drove M2 macrophage polarization by targeting macrophages in the tubulointerstitium. Our study demonstrates that EVs can serve as a promising delivery platform to manipulate IL-10 for the effective treatment of ischemic AKI.

4.
Theranostics ; 10(18): 8111-8129, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32724461

RESUMO

Dysregulated inflammation is a complicated pathological process involved in various diseases, and the treatment of inflammation-linked disorders currently represents an enormous global burden. Extracellular vesicles (EVs) are nanosized, lipid membrane-enclosed vesicles secreted by virtually all types of cells, which act as an important intercellular communicative medium. Considering their capacity to transfer bioactive substances, both unmodified and engineered EVs are increasingly being explored as potential therapeutic agents or therapeutic vehicles. Moreover, as the nature's own delivery tool, EVs possess many desirable advantages, such as stability, biocompatibility, low immunogenicity, low toxicity, and biological barrier permeability. The application of EV-based therapy to combat inflammation, though still in an early stage of development, has profound transformative potential. In this review, we highlight the recent progress in EV engineering for inflammation targeting and modulation, summarize their preclinical applications in the treatment of inflammatory disorders, and present our views on the anti-inflammatory applications of EV-based nanotherapeutics.

5.
Cell Death Dis ; 11(7): 513, 2020 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641688

RESUMO

Exosomes are increasingly recognized as vehicles of intercellular communication. However, the role of exosome in maintaining cellular homeostasis under stress conditions remained unclear. Here we show that Rab27a expression was upregulated exclusively in tubular epithelial cells (TECs) during proteinuria nephropathy established by adriamycin (ADR) injection and 5/6 nephrectomy as well as in chronic kidney disease patients, leading to the increased secretion of exosomes carrying albumin. The active exosome production promoted tubule injury and inflammation in neighboring and the producing cells. Interferon regulatory factor 1 (IRF-1) was found as the transcription factor contributed to the upregulation of Rab27a. Albumin could be detected in exosome fraction and co-localized with exosome marker CD63 indicating the secretion of albumin into extracellular space by exosomes. Interestingly, inhibition of exosome release accelerated albumin degradation which reversed tubule injury with albumin overload, while lysosome suppression augmented exosome secretion and tubule inflammation. Our findings revealed that IRF-1/Rab27a mediated exosome secretion constituted a coordinated approach to lysosome degradation for albumin handling, which lead to the augment of albumin toxicity as a maladaptive response to maintain cell homeostasis. The findings may suggest a novel therapeutic strategy for proteinuric kidney disease by targeting exosome secretion.

6.
J Pharmacol Sci ; 143(3): 226-233, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32446726

RESUMO

Renal ischemia/reperfusion (I/R) injury is a major cause of acute kidney injury (AKI), characterized by tubulointerstitial inflammation. Currently, progress in developing effective therapies to prevent or ameliorate AKI by anti-inflammation remains slow. Emerging studies have suggested that NLRP3 (the NOD-, LRR- and pyrin domain-containing 3) inflammasome plays a key role in a wide spectrum of kidney disease models including I/R injury. In this study, we investigated the renal protective effects of A68930, a specific agonist for the D-1 dopamine receptor (DRD1), which was recently recognized to downregulate NLRP3 inflammasome via DRD1 signaling. AKI was induced by renal I/R injury and A68930 was intraperitoneally injected 3 times after renal reperfusion. We showed that A68930 significantly ameliorated renal dysfunction. Meanwhile, A68930 markedly reduced macrophages and T cells infiltration, renal pro-inflammatory cytokines production (TNF-α, IL-6, IL-1ß), serum pro-inflammatory cytokine (TNF-α and IL-6) and NLRP3 inflammasome activation. Additionally, A68930 attenuated I/R-induced mitochondria injury, which was observed by transmission electron microscopy. In summary, our results demonstrated that activation of DRD1 by A68930 inhibited renal and systematic inflammation, and improved kidney function in I/R induced AKI model, which was probably related to the inhibition of the NLRP3 inflammasome activation.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/genética , Cromanos/farmacologia , Cromanos/uso terapêutico , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/metabolismo , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/prevenção & controle , Animais , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Rim/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/complicações , Fator de Necrose Tumoral alfa/metabolismo
7.
Am J Nephrol ; 51(6): 453-462, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32349004

RESUMO

BACKGROUND: The lack of consensus criteria of acute on chronic kidney injury (ACKI) affects the judgment for its clinical prognosis. METHODS: In this study, we analyzed the data from 711,615 hospitalized adults who had at least 2 serum creatinine (SCr) tests within 30 days. We estimated the reference change value (RCV) of SCr given initial SCr level in adults without known risks of acute kidney injury other than chronic kidney disease (CKD). We proposed a criterion for ACKI based on the RCV of SCr (cROCK), which defined ACKI as a ≥25% increase in SCr in 7 days. We validated cROCK by its association with the risks of in-hospital mortality, death after discharge, and CKD progression in a large cohort of patients with CKD stage 3. RESULTS: In 21,661 patients with CKD stage 3, a total of 3,145 (14.5%), 1,512 (7.0%), and 221 (1.0%) ACKI events were detected by both cROCK and Kidney Disease Improving Global Outcomes (KDIGO), cROCK only, and KDIGO only, respectively. cROCK detected 40% more ACKI events than KDIGO. Compared with patients without ACKI by both definitions, those with cROCK- but not KDIGO-defined ACKI had a significantly increased risk of in-hospital mortality (hazard ratio [HR] 5.53; 95% CI 3.75-8.16), death after discharge (HR 1.51; 95% CI 1.21-1.83), and CKD progression (OR 5.65; 95% CI 3.05-10.48). CONCLUSIONS: RCV-based criterion (cROCK) for ACKI is clinically valid in that it has a substantially improved sensitivity in identifying patients with high risk of adverse outcomes.

9.
Theranostics ; 10(6): 2803-2816, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32194836

RESUMO

Background: Our previous study demonstrated that the disruption of cholesterol homeostasis promotes tubulointerstitial injury in diabetic nephropathy (DN). This study aimed to further investigate the effects of gut microbiota dysbiosis on this process and explored its potential mechanism. Methods: Diabetic rats treated with broad-spectrum oral antibiotics or faecal microbiota transplantation (FMT) from the healthy donor group and human kidney 2 (HK-2) cells stimulated with sodium acetate were used to observe the effects of gut microbiota on cholesterol homeostasis. The gut microbiota distribution was measured by 16S rDNA sequencing with faeces. Serum acetate level was examined by gas chromatographic analysis. Protein expression of G protein coupled receptor 43 (GPR43) and molecules involved in cholesterol homeostasis were assessed by immunohistochemical staining, immunofluorescence staining, and Western Blotting. Results: Depletion of gut microbiota significantly attenuated albuminuria and tubulointerstitial injury. Interestingly, serum acetate levels were also markedly decreased in antibiotics-treated diabetic rats and positively correlated with the cholesterol contents in kidneys. An in vitro study demonstrated that acetate significantly increased cholesterol accumulation in HK-2 cells, which was caused by increased expression of proteins mainly modulating cholesterol synthesis and uptake. As expected, FMT effectively decreased serum acetate levels and alleviated tubulointerstitial injury in diabetic rats through overriding the disruption of cholesterol homeostasis. Furthermore, GPR43 siRNA treatment blocked acetate-mediated cholesterol homeostasis dysregulation in HK-2 cells through decreasing the expression of proteins governed cholesterol synthesis and uptake. Conclusion: Our studies for the first time demonstrated that the acetate produced from gut microbiota mediated the dysregulation of cholesterol homeostasis through the activation of GPR43, thereby contributing to the tubulointerstitial injury of DN, suggesting that gut microbiota reprogramming might be a new strategy for DN prevention and therapy.

11.
Acta Pharmacol Sin ; 41(8): 1111-1118, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32203081

RESUMO

Some studies have shown that gut microbiota along with its metabolites is closely associated with diabetic mellitus (DM). In this study we explored the relationship between gut microbiota and kidney injuries of early diabetic nephropathy (DN) and its underlying mechanisms. Male SD rats were intraperitoneally injected with streptozotocin to induce DM. DM rats were orally administered compound broad-spectrum antibiotics for 8 weeks. After the rats were sacrificed, their blood, urine, feces, and renal tissues were harvested for analyses. We found that compared with the control rats, DM rats had abnormal intestinal microflora, increased plasma acetate levels, increased proteinuria, thickened glomerular basement membrane, and podocyte foot process effacement in the kidneys. Furthermore, the protein levels of angiotensin II, angiotensin-converting enzyme, and angiotensin II type 1 receptor in the kidneys of DM rats were significantly increased. Administration of broad-spectrum antibiotics in DM rats not only completely killed most intestinal microflora, but also significantly lowered the plasma acetate levels, inhibited intrarenal RAS activation, and attenuated kidney damage. Finally, we showed that plasma acetate levels were positively correlated with intrarenal angiotensin II protein expression (r = 0.969, P < 0.001). In conclusion, excessive acetate produced by disturbed gut microbiota might be involved in the kidney injuries of early DN through activating intrarenal RAS.

12.
Metab Syndr Relat Disord ; 18(4): 206-211, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32069163

RESUMO

Introduction: Hyperuricemia has been associated with increased cardiovascular events in the general population. However, the role of serum uric acid (SUA) level on the severity of coronary artery stenosis (CAS) in nondialysis chronic kidney disease (CKD) patients is obscure. Methods: We implement a retrospective cohort study of 734 patients diagnosed with stage 3-5 CKD. All selected patients underwent coronary artery angiography. The associations of SUA with the present, and severity of coronary artery disease (CAD) were analyzed. Results: Of these 734 patients, 511 patients had angiographically proven CAD. Compared with non-CAD group, the SUA level in CAD group was much higher (388.00 vs. 363.00 µmol/l, P < 0.01). After adjusting for multiple confounding factors, a multivariate logistic regression analysis demonstrated that SUA was relevant to the presence of CAD when SUA as a continuous variable. However, this relationship was not observed with SUA as a categorical variable. In a subgroup analysis for the CAD group, we found that the rates of severe CAS in the third tertile of SUA (58.6%) was higher than that in the first tertile (41.6%) (P < 0.01). Compared with the first tertile of SUA, the third tertile of SUA was an independent risk factor for severe arterial stenosis (odds ratio, OR, 1.976 [1.203-3.248]), a pattern that was recapitulated by multivariate logistic regression analysis with SUA as a continuous variable (1.002 [1.000-1.004]). Conclusions: The SUA level may serve as a predictor of the severity of CAS among nondialysis CKD patients with CAD.

13.
Cell Prolif ; 53(3): e12763, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31925859

RESUMO

In recent years, although the development of clinical therapy for diabetic kidney disease (DKD) has made great progress, the progression of DKD still cannot be controlled. Therefore, further study of the pathogenesis of DKD and improvements in DKD treatment are crucial for prognosis. Traditional studies have shown that podocyte injury plays an important role in this process. Recently, it has been found that glomerulotubular balance and tubuloglomerular feedback (TGF) may be involved in the progression of DKD. Glomerulotubular balance is the specific gravity absorption of the glomerular ultrafiltrate by the proximal tubules, which absorbs only 65% to 70% of the ultrafiltrate. This ensures that the urine volume will not change much regardless of whether the glomerular filtration rate (GFR) increases or decreases. TGF is one of the significant mechanisms of renal blood flow and self-regulation of GFR, but how they participate in the development of DKD in the pathological state and the specific mechanism is not clear. Injury to tubular epithelial cells (TECs) is the key link in DKD. Additionally, injury to glomerular endothelial cells (GECs) plays a key role in the early occurrence and development of DKD. However, TECs and GECs are close to each other in anatomical position and can crosstalk with each other, which may affect the development of DKD. Therefore, the purpose of this review was to summarize the current knowledge on the crosstalk between TECs and GECs in the pathogenesis of DKD and to highlight specific clinical and potential therapeutic strategies.


Assuntos
Nefropatias Diabéticas/fisiopatologia , Glomérulos Renais/fisiopatologia , Túbulos Renais/fisiopatologia , Animais , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Progressão da Doença , Endotélio/citologia , Endotélio/metabolismo , Endotélio/patologia , Humanos , Glomérulos Renais/citologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Túbulos Renais/citologia , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Urotélio/citologia , Urotélio/metabolismo , Urotélio/patologia , Urotélio/fisiopatologia
14.
Cell Death Differ ; 27(1): 210-226, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31097789

RESUMO

Tubulointerstitial inflammation is a common characteristic of acute and chronic kidney injury. However, the mechanism by which the initial injury of tubular epithelial cells (TECs) drives interstitial inflammation remains unclear. This paper aims to explore the role of exosomal miRNAs derived from TECs in the development of tubulointerstitial inflammation. Global microRNA(miRNA) expression profiling of renal exosomes was examined in a LPS induced acute kidney injury (AKI) mouse model and miR-19b-3p was identified as the miRNA that was most notably increased in TEC-derived exosomes compared to controls. Similar results were also found in an adriamycin (ADR) induced chronic proteinuric kidney disease model in which exosomal miR-19b-3p was markedly released. Interestingly, once released, TEC-derived exosomal miR-19b-3p was internalized by macrophages, leading to M1 phenotype polarization through targeting NF-κB/SOCS-1. A dual-luciferase reporter assay confirmed that SOCS-1 was the direct target of miR-19b-3p. Importantly, the pathogenic role of exosomal miR-19b-3p in initiating renal inflammation was revealed by the ability of adoptively transferred of purified TEC-derived exosomes to cause tubulointerstitial inflammation in mice, which was reversed by inhibition of miR-19b-3p. Clinically, high levels of miR-19b-3p were found in urinary exosomes and were correlated with the severity of tubulointerstitial inflammation in patients with diabetic nephropathy. Thus, our studies demonstrated that exosomal miR-19b-3p mediated the communication between injured TECs and macrophages, leading to M1 macrophage activation. The exosome/miR-19b-3p/SOCS1 axis played a critical pathologic role in tubulointerstitial inflammation, representing a new therapeutic target for kidney disease.

15.
Sci Rep ; 9(1): 19382, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31853002

RESUMO

Muscle wasting is associated with increased mortality and morbidity in chronic kidney disease (CKD) patients, especially in the haemodialysis (HD) population. Nevertheless, little is known regarding diaphragm dysfunction in HD patients. We conducted a cross-sectional study at the Institute of Nephrology, Southeast University, involving 103 HD patients and 103 healthy volunteers as normal control. Ultrasonography was used to evaluate diaphragmatic function, including diaphragm thickness and excursion during quiet and deep breathing. HD patients showed lower end-inspiration thickness of the diaphragm at total lung capacity (0.386 ± 0.144 cm vs. 0.439 ± 0.134 cm, p < 0.01) and thickening fraction (TF) (0.838 ± 0.618 vs. 1.127 ± 0.757; p < 0.01) compared to controls. The velocity and excursion of the diaphragm were significantly lower in the HD patients during deep breathing (3.686 ± 1.567 cm/s vs. 4.410 ± 1.720 cm/s, p < 0.01; 5.290 ± 2.048 cm vs. 7.232 ± 2.365 cm; p < 0.05). Changes in diaphragm displacement from quiet breathing to deep breathing (△m) were lower in HD patients than in controls (2.608 ± 1.630 vs. 4.628 ± 2.110 cm; p < 0.01). After multivariate adjustment, diaphragmatic excursion during deep breathing was associated with haemoglobin level (regression coefficient = 0.022; p < 0.01). We also found that the incidence of dyspnoea and hiccup and the fatigue scores, all of which were related to diaphragmatic dysfunction, were significantly higher in HD patients than in controls (all p < 0.01). Improving diaphragm function through targeted therapies may positively impact clinical outcomes in HD patients.


Assuntos
Diafragma/fisiopatologia , Debilidade Muscular/fisiopatologia , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/fisiopatologia , Adulto , Estudos Transversais , Diafragma/diagnóstico por imagem , Dispneia/diagnóstico por imagem , Dispneia/fisiopatologia , Fadiga/diagnóstico por imagem , Fadiga/fisiopatologia , Feminino , Voluntários Saudáveis , Soluço/diagnóstico por imagem , Soluço/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/complicações , Debilidade Muscular/diagnóstico por imagem , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico por imagem , Capacidade Pulmonar Total/fisiologia , Ultrassonografia
16.
Clin Nephrol ; 92(6): 325-328, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31661060

RESUMO

Bartter syndrome (BS), a rare autosomal recessive disorder affecting renal tubular potassium handling, is characterized by hypokalemia, metabolic alkalosis, and renal salt wasting. In this report, we describe an adult patient with longstanding clinical symptoms of fatigue, polyuria, polydipsia, mental retardation, and physical dysplasia along with hypokalemia and metabolic alkalosis as laboratory findings. With these clinical symptoms, a patient can be diagnosed with BS type III. Renal biopsy and genetic testing were performed for further confirmation of the diagnosis, revealing renin granular deposits in the juxtaglomerular apparatus (JA) with JA hyperplasia. DNA sequencing detected a heterozygous synonymous mutation, c.1140G>A, in exon 12 of the CLCNKB gene, which could be traced back to a heterozygous synonymous mutation in the patient's mother, who does not have BS.


Assuntos
Síndrome de Bartter/genética , Canais de Cloreto/genética , Mutação Silenciosa , Adulto , Feminino , Humanos
17.
Ann Transl Med ; 7(14): 312, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31475182

RESUMO

Background: Recently, cinacalcet (CINA) has been shown to be effective for attenuating bone loss in the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD), which might be associated with the reduction in serum parathyroid hormone (PTH) levels. However, the exact mechanism is largely unclear. Emerging studies have revealed that an increased number of bone marrow adipocytes (BMAs) are involved in bone loss and the endothelial-to-adipocyte transition via the endothelial-to-mesenchymal transition (EndMT) might play a key role in this pathological process. Here, we assessed whether CINA could attenuate bone loss via inhibiting endothelial-to-adipocyte transition in CKD rats. Methods: A rat model of CKD was induced by adenine and a high phosphorus diet. CINA was orally administrated to CKD animals (10 mg/kg once a day). Dual energy X-ray absorptiometry, micro-computed tomography, bone histomorphometry, and bone mechanical tests were used to determine the skeletal changes. The bone marrow expression of EndMT markers was also examined. The effect of elevated PTH levels on the endothelial-to-adipocyte transition was studied in endothelial cells (ECs). Results: Elevation of serum PTH levels, remarkable bone loss and increased numbers of BMAs were observed in rats with CKD compared with the controls, and these changes were attenuated after treatment with CINA. Furthermore, the CINA treatment abolished the upregulation of mesenchymal markers (FSP1 and α-SMA) and the downregulation of an endothelial marker (CD31) in bone tissues from rats with CKD. The serum PTH concentrations were correlated with the bone marrow protein levels of these EndMT-related proteins. An in vitro treatment in ECs demonstrated that PTH induced the EndMT in a concentration- and time-dependent manner. Accordingly, ECs treated with PTH exhibited adipogenic potential following growth in adipogenic culture medium. Conclusions: Our study indicated CINA treatment attenuated bone loss in CKD rats, which might be associated with inhibiting PTH-induced endothelial-to-adipocyte transition in CKD rats.

18.
Ann Transl Med ; 7(14): 322, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31475192

RESUMO

Background: We conducted a network meta-analysis (NMA) to evaluate the efficacy and safety of cinacalcet, active vitamin D and cinacalcet plus active vitamin D in the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD). Methods: A systematic literature search was performed using the Cochrane Library, PubMed, EMBASE, Web of Science, Google Scholar, China National Knowledge Internet (CNKI) and Wanfang databases. In total, eight randomized controlled trials (RCTs) with 1,443 patients were eligible for this meta-analysis. Pairwise meta-analysis was performed to evaluate the compliance of intact parathyroid hormone (iPTH), Ca, P, etc., and the mortality and safety of cinacalcet plus active vitamin D and active vitamin D alone. Then, NMA was used to estimate the safety and efficacy of the administration of active vitamin D and different drugs in the control group. Results: The results of the pairwise meta-analysis revealed that compared with active vitamin D monotherapy, cinacalcet plus active vitamin D did not improve the survival of patients but significantly improved the blood calcium compliance rate [relative risk (RR) =1.82, 95% confidence interval (CI): 1.51-2.21, P<0.00001]. Furthermore, it is worth noting that compared with the corresponding incidence with other treatments, the incidence of vomiting was significantly increased with cinacalcet plus active vitamin D treatment (RR =2.07, 95% CI: 1.18-3.65, P=0.01). Through direct and indirect comparisons, the NMA revealed the following results: (I) compared with oral or intravenous (IV) administration of vitamin D, the solely oral administration of active vitamin D increased mortality, and (II) cinacalcet monotherapy increased the risk of hypocalcemia, and that risk was even higher for cinacalcet plus active vitamin D. However, the results should be treated with caution because the prediction interval (PrI) crossed the invalid line. Conclusions: This pairwise meta-analysis and NMA provided a comprehensive analysis of the currently utilized CKD-SHPT treatment interventions. This network identified some highly ranked interventions through analyses that were included in a small number of trials; these interventions merit further examination on a larger scale in the context of well-designed RCTs.

19.
Front Pharmacol ; 10: 880, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31447676

RESUMO

Acute kidney injury leading to chronic kidney disease through tubulointerstitial fibrosis is a major challenge in nephropathy. Several signaling pathways promote interstitial fibrosis; however, effective suppression of fibrosis may require blockade of more than one pathway. This study investigated whether blockade of Smad3 and c-Jun N-terminal kinase (JNK) signaling gives added suppression of interstitial fibrosis in folic acid nephropathy. A single high dose of folic acid (FA) causes acute tubular damage in C57BL/6J mice followed by interstitial fibrosis and chronic renal impairment. Co-activations of Smad3 and JNK signaling occur in both tubular epithelial cells and myofibroblasts in areas of tubulointerstitial damage and fibrosis in both murine FA-induced nephropathy and human IgA nephropathy. Groups of mice were treated with a Smad3 inhibitor (SIS3), a JNK inhibitor (SP600125), or a combination from day 6 after FA administration until being killed on day 28. Each drug efficiently inhibited its specific target (Smad3 phosphorylation or c-Jun phosphorylation) without affecting the other pathway. Given alone, each drug partially reduced renal fibrosis, whereas the combination therapy gave an additive and profound protection from renal fibrosis and improved renal function. Inhibition of Smad3 and/or JNK signaling activities prevented down-regulation of PGC-1α in tubular epithelial cells and up-regulation of PGC-1α in myofibroblasts during FA-induced renal fibrosis and inflammation. The expression of PGC-1α was upregulated in Smad3 -/- NRK52E cells while downregulated in Smad3 -/- NRK49F cells, suggesting that Smad3 signaling may regulate expression of PGC-1α in renal tubular epithelial cells and fibroblasts in distinct fashion. In vivo and cell culture studies also indicate that Smad3 and JNK signaling cooperate to cause mitochondrial dysfunction and cell damage in tubular epithelial cells via direct actions on the transcription of PGC-1α. These pathways also act cooperatively to promote renal fibroblast proliferation in tempo-spatial fashion. In conclusion, we have identified a potential combination therapy for progressive renal fibrosis which operates, in part, through modifying mitochondrial function.

20.
FASEB J ; 33(11): 12630-12643, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31451021

RESUMO

The discovery of hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor (PHI) has revolutionized the treatment strategy for renal anemia. However, the presence of multiple transcription targets of HIF raises safety concerns regarding HIF-PHI. Here, we explored the dose-dependent effect of MK-8617 (MK), a kind of HIF-PHI, on renal fibrosis. MK was administered by oral gavage to mice for 12 wk at doses of 1.5, 5, and 12.5 mg/kg. In vitro, the human proximal tubule epithelial cell line HK-2 was treated with increasing doses of MK administration. Transcriptome profiling was performed, and fibrogenesis was evaluated. The dose-dependent biphasic effects of MK on tubulointerstitial fibrosis (TIF) were observed in chronic kidney disease mice. Accordingly, high-dose MK treatment could significantly enhance TIF. Using RNA-sequencing, combined with in vivo and in vitro experiments, we found that Krüppel-like factor 5 (KLF5) expression level was significantly increased in the proximal tubular cells, which could be transcriptionally regulated by HIF-1α with high-dose MK treatment but not low-dose MK. Furthermore, our study clarified that HIF-1α-KLF5-TGF-ß1 signaling activation is the potential mechanism of high-dose MK-induced TIF, as knockdown of KLF5 reduced TIF in vivo. Collectively, our study demonstrates that high-dose MK treatment initiates TIF by activating HIF-1α-KLF5-TGF-ß1 signaling. These findings provide novel insights into TIF induction by high-dose MK (HIF-PHI), suggesting that the safety dosage window needs to be emphasized in future clinical applications.-Li, Z.-L., Lv, L.-L., Wang, B., Tang, T.-T., Feng, Y., Cao, J.-Y., Jiang, L.-Q., Sun, Y.-B., Liu, H., Zhang, X.-L., Ma, K.-L., Tang, R.-N., Liu, B.-C. The profibrotic effects of MK-8617 on tubulointerstitial fibrosis mediated by the KLF5 regulating pathway.

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