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2.
Diabetes Metab Syndr Obes ; 15: 799-811, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35313680

RESUMO

Purpose: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide. Risk assessment provides information about patient prognosis, contributing to the risk stratification of patients and the rational allocation of medical resources. We aimed to develop a model for individualized prediction of renal function decline in patients with type 2 DKD (T2DKD). Patients and Methods: In a retrospective observational study, we followed 307 T2DKD patients and evaluated the determinants of 1) risk of doubling in serum creatinine (Scr), 2) risk of eGFR<15 mL/min/1.73m2 using potential risk factors at baseline. A prediction model represented by a nomogram and a risk table was developed using Cox regression and externally validated in another cohort with 206 T2DKD patients. The discrimination and calibration of the prediction model were evaluated by the concordance index (C-index) and calibration curve, respectively. Results: Four predictors were selected to establish the final model: Scr, urinary albumin/creatinine ratio, plasma albumin, and insulin treatment. The nomogram achieved satisfactory prediction performance, with a C-index of 0.791 [95% confidence interval (CI) 0.762-0.820] in the derivation cohort and 0.793 (95% CI 0.746-0.840) in the external validation cohort. Then, all predictors were scored according to their weightings. A risk table with the highest score of 11.5 was developed. The C-index of the risk table was 0.764 (95% CI: 0.731-0.797), which was similar to the external validation cohort (0.763; 95% CI: 0.714-0.812). Additionally, the patients were divided into two groups based on the risk table, and significant differences in the probability of outcome events were observed between the high-risk (score >2) and low-risk (score ≤2) groups in the derivation and external validation cohorts (P < 0.001). Conclusion: The nomogram and the risk table using readily available clinical parameters could be new tools for bedside prediction of renal function decline in T2DKD patients.

3.
Clin Kidney J ; 15(3): 534-544, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35211307

RESUMO

BACKGROUND: Urinary sediment messenger RNAs (mRNAs) have been shown as novel biomarkers of kidney disease. We aimed to identify targeted urinary mRNAs in diabetic nephropathy (DN) based on bioinformatics analysis and clinical validation. METHODS: Microarray studies of DN were searched in the GEO database and Nephroseq platform. Gene modules negatively correlated with estimated glomerular filtration rate (eGFR) were identified by informatics methods. Hub genes were screened within the selected modules. In validation cohorts, a quantitative polymerase chain reaction assay was used to compare the expression levels of candidate mRNAs. Patients with renal biopsy-confirmed DN were then followed up for a median time of 21 months. End-stage renal disease (ESRD) was defined as the primary endpoint. Multivariate Cox proportional hazards regression was developed to evaluate the prognostic values of candidate mRNAs. RESULTS: Bioinformatics analysis revealed four chemokines (CCL5, CXCL1, CXLC6 and CXCL12) as candidate mRNAs negatively correlated with eGFR, of which CCL5 and CXCL1 mRNA levels were upregulated in the urinary sediment of patients with DN. In addition, urinary sediment mRNA of CXCL1 was negatively correlated with eGFR (r = -0.2275, P = 0.0301) and CCL5 level was negatively correlated with eGFR (r = -0.4388, P < 0.0001) and positively correlated with urinary albumin:creatinine ratio (r = 0.2693, P = 0.0098); also, CCL5 and CXCL1 were upregulated in patients with severe renal interstitial fibrosis. Urinary sediment CCL5 mRNA was an independent predictor of ESRD [hazard ratio 1.350 (95% confidence interval 1.045-1.745)]. CONCLUSIONS: Urinary sediment CCL5 and CXCL1 mRNAs were upregulated in DN patients and associated with a decline in renal function and degree of renal interstitial fibrosis. Urinary sediment CCL5 mRNA could be used as a potential prognostic biomarker of DN.

4.
Sheng Li Xue Bao ; 74(1): 59-66, 2022 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-35199126

RESUMO

Vascular endothelial growth factor-A (VEGF-A) is a critical angiogenic factor which is mainly secreted from podocytes and epithelial cells in kidney and plays an important role in renal pathophysiology. In recent years, functions of different isoforms of VEGF-A and the new secretion approach via extracellular vesicles (EVs) have been identified. Thus, further understanding are needed for the role of VEGF-A and its isoforms in renal injury and repair. In this review, we summarized the expression, secretion and regulation of VEGF-A, its biological function, and the role of different isoforms of VEGF-A in the development of different renal diseases. Meanwhile, the research progress of VEGF-A as diagnostic marker and therapeutic target for renal diseases were discussed.


Assuntos
Nefropatias , Fator A de Crescimento do Endotélio Vascular/metabolismo , Humanos , Rim/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/fisiologia
5.
Sheng Li Xue Bao ; 74(1): 67-72, 2022 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-35199127

RESUMO

Extracellular vesicles (EVs) are lipid bilayer-enclosed structures containing diverse bioactive cargoes that play a major role in intercellular communication in both physiological and pathological conditions. Currently, the field of EV-based therapy has been rapidly growing, and two main therapeutic uses of EVs can be surmised: (i) exploiting stem cell-derived EVs as therapeutic agents; and (ii) employing EVs as natural therapeutic vectors for drug delivery. This review will discuss the recent advances in EV-based therapy in the treatment of renal disease.


Assuntos
Vesículas Extracelulares , Nefropatias , Comunicação Celular , Sistemas de Liberação de Medicamentos , Humanos , Nefropatias/terapia
6.
Artigo em Inglês | MEDLINE | ID: mdl-35044244

RESUMO

Significance: The disturbance of the hypoxia response system is closely related to human diseases, because it is essential for the maintenance of homeostasis. Given the significant role of the hypoxia response system in human health, therapeutic applications targeting prolyl hydroxylase-hypoxia-inducible factor (HIF) signaling have been attempted. Thus, systemically reviewing the hypoxia response-based therapeutic strategies is of great significance. Recent Advances: Disturbance of the hypoxia response is a characteristic feature of various diseases. Targeting the hypoxia response system is, thus, a promising therapeutic strategy. Interestingly, several compounds and drugs are currently under clinical trials, and some have already been approved for use in the treatment of certain human diseases. Critical Issues: We summarize the molecular mechanisms of the hypoxia response system and address the potential therapeutic implications in kidney diseases. Given that the effects of hypoxia response in kidney diseases are likely to depend on the pathological context, specific cell types, and the differences in the activation pattern of HIF isoforms, the precise application is critical for the treatment of kidney diseases. Although HIF-PHIs (HIF-PHD inhibitors) have been proven to be effective and well tolerated in chronic kidney disease patients with anemia, the potential on-target consequence of HIF activation and some outstanding questions warrant further consideration. Future Direction: The mechanism of the hypoxia response system disturbance remains unclear. Elucidation of the molecular mechanism of hypoxia response and its precise effects on kidney diseases warrants clarification. Considering the complexity of the hypoxia response system and multiple biological processes controlled by HIF signaling, the development of more specific inhibitors is highly warranted.

7.
J Clin Hypertens (Greenwich) ; 24(3): 300-308, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35099841

RESUMO

Growing evidences have confirmed the effect of Sacubitril/Valsartan (SV) on antihypertension and cardiac protection in general population. However, there was no prospective study about the effect and safety of SV on resistant hypertension and myocardial work in hemodialysis patients. In this single-center, prospective, before-after study, enrolled patients were endured with resistant hypertension for more than 6 months. Participants were initially instructed to take SV 50 mg twice daily, and the dosage was gradually increased up to 100 mg twice daily. The primary outcomes were blood pressure (BP) control, N-terminal pro-B-type natriuretic peptide (NT-proBNP), myocardial work (MW), fatigue and life quality. In addition, the adverse events were also recorded in this cohort. A total of 18 patients (34-64 years old) was finally enrolled and completed in this study. The SV-based regimen provided significantly mean sitting systolic BP (msSBP) and mean sitting diastolic BP (msDBP) reductions from baseline (-20.7/-8.3 mm Hg), respectively. The cardiac remodeling parameters were partially improved. Compared to the baseline, NT-proBNP was significantly reduced at week 4 (8119.50 [3710.75, 29300] pg/ml to 7216.50 [4124.75, 17455.00] pg/ml, p = .046), which was much lower at week 12 (3130.50 [2244.50, 9565.70] pg/ml, p = .037). Global MW index was higher at week 12 compared to the baseline (p = .026). MW efficiency was also improved accordingly compared to the baseline, even though the statistical difference was not significant (p = .226). Life quality and fatigue were improved at week 12 compared to the baseline (all p = .000). There was no serious adverse events were observed. SV safely and effectively controlled resistant hypertension and improved MW as well as life quality in hemodialysis patients.


Assuntos
Aminobutiratos , Compostos de Bifenilo , Coração , Hipertensão , Diálise Renal , Valsartana , Adulto , Aminobutiratos/efeitos adversos , Compostos de Bifenilo/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Fadiga/induzido quimicamente , Coração/efeitos dos fármacos , Humanos , Hipertensão/tratamento farmacológico , Pessoa de Meia-Idade , Estudos Prospectivos , Valsartana/efeitos adversos
8.
Int J Biol Sci ; 18(1): 96-111, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34975320

RESUMO

Background: G-protein-coupled receptor 43 (GPR43) is a posttranscriptional regulator involved in cholesterol metabolism. This study aimed to investigate the possible roles of GPR43 activation in podocyte lipotoxicity in diabetic nephropathy (DN) and explore the potential mechanisms. Methods: The experiments were conducted by using diabetic GPR43-knockout mice and a podocyte cell culture model. Lipid deposition and free cholesterol levels in kidney tissues were measured by BODIPY staining and quantitative cholesterol assays, respectively. The protein expression of GPR43, LC3II, p62, beclin1, low-density lipoprotein receptor (LDLR) and early growth response protein 1 (EGR1) in kidney tissues and podocytes was measured by real-time PCR, immunofluorescent staining and Western blotting. Results: There were increased LDL cholesterol levels in plasma and cholesterol accumulation in the kidneys of diabetic mice. However, GPR43 gene knockout inhibited these changes. An in vitro study further demonstrated that acetate treatment induced cholesterol accumulation in high glucose-stimulated podocytes, which was correlated with increased cholesterol uptake mediated by LDLR and reduced cholesterol autophagic degradation, as characterized by the inhibition of LC3 maturation, p62 degradation and autophagosome formation. Gene knockdown or pharmacological inhibition of GPR43 prevented these effects on podocytes. Furthermore, GPR43 activation increased extracellular regulated protein kinases 1/2 (ERK1/2) activity and EGR1 expression in podocytes, which resulted in an increase in cholesterol influx and autophagy inhibition. In contrast, after GPR43 deletion, these changes in podocytes were improved, as shown by the in vivo and in vitro results. Conclusion: GPR43 activation-mediated lipotoxicity contributes to podocyte injury in DN by modulating the ERK/EGR1 pathway.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Metabolismo dos Lipídeos , Sistema de Sinalização das MAP Quinases , Podócitos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Modelos Animais de Doenças , Camundongos , Receptores de LDL/metabolismo
9.
Semin Dial ; 35(1): 40-49, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34816483

RESUMO

BACKGROUND: Dialysis unit blood pressure (BP) pattern showed superiority in prognostic evaluation and interdialytic BP burden assessment. However previous studies mainly focused on the recurrent BP pattern within a session (intradialytic BP change or intradialytic BP slope), the clinical value of the weekly pattern of dialysis unit BP is unknown. METHODS: We performed a prospective cohort study in adult end stage renal disease (ESRD) patients on thrice weekly hemodialysis (HD). The slope and the change of the postdialysis systolic BP (SBP) in the course of a week (post-SBP slope and post-SBP change) were used to characterize the weekly pattern of dialysis unit BP. Outcomes included all-cause mortality, cardiovascular mortality, and first cardiovascular event. We also measured the home BP in our cohort. RESULTS: One hundred and twenty-nine subjects were followed over a median of 31 months. Higher post-SBP slope (≥0.185) was independently associated with increased risk of all-cause mortality, cardiovascular mortality, and first cardiovascular event. Results were similar for increased post-SBP change. HD patients with a higher post-SBP slope or an increased post-SBP change also had significant increased interdialytic BP burden measured by home SBP on both dialysis days and non-dialysis days. CONCLUSIONS: Post-SBP slope and post-SBP change might be promising dialysis unit BP markers for prognostic evaluation and interdialytic BP burden assessment.


Assuntos
Hipertensão , Falência Renal Crônica , Adulto , Pressão Sanguínea/fisiologia , Feminino , Humanos , Hipertensão/etiologia , Falência Renal Crônica/complicações , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/terapia , Masculino , Prognóstico , Estudos Prospectivos , Diálise Renal/efeitos adversos
10.
EBioMedicine ; 77: 103942, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35290825

RESUMO

Hypoxia is an inherent pathophysiological characteristic of chronic kidney disease (CKD), which is closely associated with the development of renal inflammation and fibrosis, as well as CKD-related complications such as anaemia, cardiovascular events, and sarcopenia. This review outlined the characteristics of oxygen supply in the kidney, changes in oxygen metabolism and factors leading to hypoxia in CKD. Mechanistically, we discussed how hypoxia contributes to renal injury as well as complications associated with CKD. Furthermore, we also discussed the potential therapeutic approaches that target chronic hypoxia, as well as the challenges in the study of oxygen homeostasis imbalance in CKD.


Assuntos
Insuficiência Renal Crônica , Fibrose , Humanos , Hipóxia/complicações , Rim/irrigação sanguínea , Insuficiência Renal Crônica/complicações
11.
Cell Death Dis ; 12(10): 866, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34556635

RESUMO

Tubules injury and immune cell activation are the common pathogenic mechanisms in acute kidney injury (AKI). However, the exact modes of immune cell activation following tubule damage are not fully understood. Here we uncovered that the release of cytoplasmic spliceosome associated protein 130 (SAP130) from the damaged tubular cells mediated necroinflammation by triggering macrophage activation via miRNA-219c(miR-219c)/Mincle-dependent mechanism in unilateral ureteral obstruction (UUO) and cisplatin-induced AKI mouse models, and in patients with acute tubule necrosis (ATN). In the AKI kidneys, we found that Mincle expression was tightly correlated to the necrotic tubular epithelial cells (TECs) with higher expression of SAP130, a damaged associated molecule pattern (DAMP), suggesting that SAP130 released from damaged tubular cells may trigger macrophage activation and necroinflammation. This was confirmed in vivo in which administration of SAP130-rich supernatant from dead TECs or recombinant SAP130 promoted Mincle expression and macrophage accumulation which became worsen with profound tubulointerstitial inflammation in LPS-primed Mincle WT mice but not in Mincle deficient mice. Further studies identified that Mincle was negatively regulated via miR-219c-3p in macrophages as miR-219c-3p bound Mincle 3'-UTR to inhibit Mincle translation. Besides, lentivirus-mediated renal miR-219c-3p overexpression blunted Mincle and proinflammatory cytokine expression as well as macrophage infiltration in the inflamed kidney of UUO mice. In conclusion, SAP130 is released by damaged tubules which elicit Mincle activation on macrophages and renal necroinflammation via the miR-219c-3p-dependent mechanism. Results from this study suggest that targeting miR-219c-3p/Mincle signaling may represent a novel therapy for AKI.


Assuntos
Injúria Renal Aguda/genética , Injúria Renal Aguda/patologia , Inflamação/patologia , Túbulos Renais/patologia , Lectinas Tipo C/metabolismo , Proteínas de Membrana/metabolismo , MicroRNAs/metabolismo , Proteínas/metabolismo , Transdução de Sinais , Regiões 3' não Traduzidas/genética , Adulto , Animais , Sequência de Bases , Estudos de Casos e Controles , Morte Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Lectinas Tipo C/genética , Ativação de Macrófagos , Macrófagos/metabolismo , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Pessoa de Meia-Idade , Necrose , Células RAW 264.7
12.
Front Genet ; 12: 690952, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34349783

RESUMO

Complement factor B (CFB) variants have been described to play a causative role in auto-immune associated C3 glomerulopathy (C3G) and/or atypical hemolytic uremic syndrome (aHUS) by affecting the dysregulations of alternative pathway activation. However, CFB variant concomitant with COL4A5 variant is scarce. Here, we depict two intriguing cases with concurrent novel heterozygosity for CFB c.2054_2057del (p.Ser687Profs∗16) variant and a previous reported COL4A5 c.2999G > T (p.Gly1000Val) variant in a pair of siblings. The clinical feature of either paternal CFB variant or maternal COL4A5 variant is just mild microscopic hematuria. Interestingly, their two children with paternal CFB c.2054_2057del (p.Ser687Profs∗16) variant and maternal COL4A5 c.2999G > T (p.Gly1000Val) variant presented with massive proteinuria, hematuria, and progressive renal failure with poor treatment response. Moreover, complement pathway activation in renal tissue further supports and strengthens the pathogenic role of CFB variant in the development of renal injury in the presence of COL4A5 variant. In conclusion, the rare sibling cases highlight that the extension of genetic analyses in the proband is helpful for the diagnosis and understanding of some family cluster renal diseases.

13.
J Transl Med ; 19(1): 355, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404433

RESUMO

BACKGROUND: Diabetic nephropathy (DN) is a leading cause of renal failure, whereas the effective and early diagnostic biomarkers are still lacking. METHODS: Fourteen cytokines and chemokines mRNA were detected in urinary extracellular vesicles (EVs) from the screening cohort including 4 healthy controls (HC), 4 diabetes mellitus (DM) and 4 biopsy-proven DN patients, and was validated in another 16 HC and 15 DM and 28 DN patients. Correlation analysis was performed between the candidate biomarkers and clinic parameters as well as kidney histological changes. The findings were also confirmed in DN rat model with single injection of STZ. RESULTS: The number of small EVs secreted in urine was increased in DN patients compared to DM patients and healthy controls, with expression of AQP1 (a marker of proximal tubules) and AQP2 (a marker of distal/collecting tubules). Small EVs derived CCL21 mRNA increased significantly in DN patients and correlated with level of proteinuria and eGFR. Interestingly, elevated CCL21 mRNA from urine small EVs was observed in DN patients with normal renal function and could discriminate early DN patients from DM more efficiently compared to eGFR and proteinuria. CCL21 also showed an accurate diagnostic ability in distinguishing incipient from overt DN. Histologically, CCL21 mRNA expression increased progressively with the deterioration of tubulointerstitial inflammation and showed the highest level in nodular sclerosis group (class III) in DN patients. Remarkable infiltration of CD3 positive T cells including both CD4 and CD8 positive T cell population were observed in DN patients with high-CCL21 expression. Besides, accumulation of CD3 positive T cells correlated with level of urinary small EVs derived CCL21 and co-localized with CCL21 in the tubulointerstitium in DN patients. Finally, the correlation of CCL21 expression in renal cortex and urinary small EVs was confirmed in STZ-induced DN rat model. CONCLUSIONS: Urinary small EVs derived CCL21 mRNA may serve as early biomarker for identifying DN linked with pathogenesis. CCL21 mRNA mediated T cell infiltration may constitute the key mechanism of chronic inflammation in DN.


Assuntos
Quimiocina CCL21 , Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Vesículas Extracelulares , Animais , Aquaporina 2 , Biomarcadores , Quimiocina CCL21/genética , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/genética , Humanos , RNA Mensageiro/genética , Ratos
14.
Diabetes ; 70(11): 2639-2651, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34376476

RESUMO

Foot process effacement is an important feature of early diabetic nephropathy (DN), which is closely related to the development of albuminuria. Under certain nephrotic conditions, the integrity and function of the glomerular slit diaphragm (SD) structure were impaired and replaced by the tight junction (TJ) structure, resulting in so-called SD-TJ transition, which could partially explain the effacement of foot processes at the molecular level. However, the mechanism underlying the SD-TJ transition has not been described in DN. Here, we demonstrated that impaired autophagic flux blocked p62-mediated degradation of ZO-1 (TJ protein) and promoted podocytes injury via activation of caspase3 and caspase8. Interestingly, the expression of VDR in podocytes was decreased under diabetes conditions, which impaired autophagic flux through downregulating Atg3. Of note, we also found that VDR abundance was negatively associated with impaired autophagic flux and SD-TJ transition in the glomeruli from human renal biopsy samples with DN. Furthermore, VDR activation improved autophagic flux and attenuated SD-TJ transition in the glomeruli of diabetic animal models. In conclusion, our data provided the novel insight that VDR/Atg3 axis deficiency resulted in SD-TJ transition and foot processes effacement via blocking the p62-mediated autophagy pathway in DN.


Assuntos
Proteínas Relacionadas à Autofagia/metabolismo , Autofagia/fisiologia , Nefropatias Diabéticas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Receptores de Calcitriol/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo , Animais , Proteínas Relacionadas à Autofagia/genética , Conservadores da Densidade Óssea/farmacologia , Caspase 3/genética , Caspase 3/metabolismo , Caspase 8/genética , Caspase 8/metabolismo , Células Cultivadas , Nefropatias Diabéticas/patologia , Regulação para Baixo , Ergocalciferóis/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Rim/citologia , Glomérulos Renais/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Podócitos/metabolismo , Proteínas de Ligação a RNA/genética , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/deficiência , Receptores de Calcitriol/genética , Junções Íntimas , Enzimas de Conjugação de Ubiquitina/genética , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismo
15.
Am J Physiol Renal Physiol ; 321(2): F225-F235, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34229478

RESUMO

Oxygen homeostasis disturbances play a critical role in the pathogenesis of acute kidney injury (AKI). The transcription factor hypoxia-inducible factor-1 (HIF-1) is a master regulator of adaptive responses to hypoxia. Aside from posttranslational hydroxylation, the mechanism of HIF-1 regulation in AKI remains largely unclear. In this study, the mechanism of HIF-α regulation in AKI was investigated. We found that tubular HIF-1α expression significantly increased at the transcriptional level in ischemia-reperfusion-, unilateral ureteral obstruction-, and sepsis-induced AKI models, which was closely associated with macrophage-dependent inflammation. Meanwhile, NF-κB, which plays a central role in the inflammation response, was involved in the increasing expression of HIF-1α in AKI, as evidenced by pharmacological modulation (NF-κB inhibitor BAY11-7082). Mechanistically, NF-κB directly bound to the HIF-1α promoter and enhanced its transcription, which occurred not only under hypoxic conditions but also under normoxic conditions. Moreover, the induced HIF-1α by inflammation protected against tubular injury in AKI. Thus, our findings not only provide novel insights into HIF-1 regulation in AKI but also offer to understand the pathophysiology of kidney diseases.NEW & NOTEWORTHY Here, the mechanism of hypoxia-inducible factor-α (HIF-α) regulation in acute kidney injury (AKI) was investigated. We found that tubular HIF-1α expression significantly increased at the transcriptional level, which was closely associated with macrophage-dependent inflammation. Meanwhile, NF-κB was involved in the increasing expression of HIF-1α in AKI. Mechanistically, NF-κB directly bound to the HIF-1α promoter and enhanced its transcription. Our findings not only provide novel insights into HIF-1 regulation in AKI but also offer to understand the pathophysiology of kidney diseases.


Assuntos
Injúria Renal Aguda/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Rim/metabolismo , NF-kappa B/metabolismo , Injúria Renal Aguda/genética , Animais , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Inflamação/genética , Inflamação/metabolismo , Rim/efeitos dos fármacos , Camundongos , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , Nitrilas/farmacologia , Sulfonas/farmacologia
16.
Clin Kidney J ; 14(6): 1697-1700, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34084467

RESUMO

Immunoglobulin A (IgA) nephropathy, in the presence of myeloid bodies, has been reported in Fabry disease (FD). In this case, we excluded the diagnosis of FD by demonstrating the absence of mutation in the α-galactosidase A(GLA)gene. Our patient also denied any history of use of cationic amphiphilic drugs. Interestingly, we identified a novel missense mutation for Coenzyme Q2(COQ2) , which is known to cause COQ2 mutation-associated nephropathy. We also found heteromorphic mitochondria and good treatment response in our patient following coenzyme Q10 supplementation. In light of our findings, our patient was diagnosed with COQ2 nephropathy and IgA nephropathy. To our knowledge, this is the first case report of COQ2 nephropathy with pathologic manifestations of myeloid bodies in podocytes.

17.
Front Immunol ; 12: 681748, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093584

RESUMO

Kidney macrophages are central in kidney disease pathogenesis and have therapeutic potential in preventing tissue injury and fibrosis. Recent studies highlighted that kidney macrophages are notably heterogeneous immune cells that fulfill opposing functions such as clearing deposited pathogens, maintaining immune tolerance, initiating and regulating inflammatory responses, promoting kidney fibrosis, and degrading the extracellular matrix. Macrophage origins can partially explain macrophage heterogeneity in the kidneys. Circulating Ly6C+ monocytes are recruited to inflammatory sites by chemokines, while self-renewed kidney resident macrophages contribute to kidney repair and fibrosis. The proliferation of resident macrophages or infiltrating monocytes provides an alternative explanation of macrophage accumulation after kidney injury. In addition, dynamic Ly6C expression on infiltrating monocytes accompanies functional changes in handling kidney inflammation and fibrosis. Mechanisms underlying kidney macrophage heterogeneity, either by recruiting monocyte subpopulations, regulating macrophage polarization, or impacting distinctive macrophage functions, may help develop macrophage-targeted therapies for kidney diseases.


Assuntos
Nefropatias/etiologia , Nefropatias/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Animais , Biomarcadores , Plasticidade Celular/imunologia , Suscetibilidade a Doenças , Fibrose , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Nefropatias/patologia , Monócitos/imunologia , Monócitos/metabolismo , Especificidade de Órgãos/imunologia , Análise de Célula Única
18.
Kidney Dis (Basel) ; 7(3): 227-240, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34179118

RESUMO

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in haemodialysis (HD) patients. Vascular calcification (VC) is dramatically accelerated and is strongly associated with CVD events and mortality in HD patients. VC coexists with osteoporosis in many studies. Fibroblast growth factor 21 (FGF21) which is known as an adipocytokine is a new hypoglycemic strategy and is inversely related to bone mineral density. METHODS: To evaluate the contribution of FGF21 to VC in HD patients, we detected circulating FGF21 levels and measured the whole thoracic aorta calcification scores (TACS) and calcification scores of the 3 segments of thoracic aorta, including ascending thoracic aorta (ATACS), aortic arch (AoACS), and descending thoracic aorta (DTACS) of our HD patients in this cross-sectional study. In addition, we pre-incubated human aortic endothelial cells (HAECs) with FGF21 in the presence or absence of parathyroid hormone (PTH) in vitro. RESULTS: The median serum FGF21 level in HD patients was 11-fold higher than that in healthy controls. Ln(FGF21) was positively correlated with Ln(TACS+1), Ln(ATACS+1), Ln(AoACS+1), and Ln(DTACS+1), respectively, in HD patients. Serum FGF21 was independently associated with TACS and ATACS, AoACS, and DTACS. FGF21 which was combined with age, calcium, and intact PTH demonstrated a high area under the curve of 0.84 with optimal sensitivity (84%) and specificity (71%) for the prediction of VC in HD patients. Our vitro results showed that FGF21 enhanced the calcification effect of PTH on HAECs by increasing calcium deposition and endothelial-to-mesenchymal transition. CONCLUSIONS: Circulating FGF21 was notably higher and was a potential predictor and promoter of VC in HD patients.

19.
J Am Soc Nephrol ; 32(10): 2467-2483, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34127536

RESUMO

BACKGROUND: AKI is a significant public health problem with high morbidity and mortality. Unfortunately, no definitive treatment is available for AKI. RNA interference (RNAi) provides a new and potent method for gene therapy to tackle this issue. METHODS: We engineered red blood cell-derived extracellular vesicles (REVs) with targeting peptides and therapeutic siRNAs to treat experimental AKI in a mouse model after renal ischemia/reperfusion (I/R) injury and unilateral ureteral obstruction (UUO). Phage display identified peptides that bind to the kidney injury molecule-1 (Kim-1). RNA-sequencing (RNA-seq) characterized the transcriptome of ischemic kidney to explore potential therapeutic targets. RESULTS: REVs targeted with Kim-1-binding LTH peptide (REVLTH) efficiently homed to and accumulated at the injured tubules in kidney after I/R injury. We identified transcription factors P65 and Snai1 that drive inflammation and fibrosis as potential therapeutic targets. Taking advantage of the established REVLTH, siRNAs targeting P65 and Snai1 were efficiently delivered to ischemic kidney and consequently blocked the expression of P-p65 and Snai1 in tubules. Moreover, dual suppression of P65 and Snai1 significantly improved I/R- and UUO-induced kidney injury by alleviating tubulointerstitial inflammation and fibrosis, and potently abrogated the transition to CKD. CONCLUSIONS: A red blood cell-derived extracellular vesicle platform targeted Kim-1 in acutely injured mouse kidney and delivered siRNAs for transcription factors P65 and Snai1, alleviating inflammation and fibrosis in the tubules.


Assuntos
Injúria Renal Aguda/terapia , Vesículas Extracelulares , Terapia Genética/métodos , Receptor Celular 1 do Vírus da Hepatite A/genética , Fatores de Transcrição da Família Snail/genética , Fator de Transcrição RelA/genética , Injúria Renal Aguda/patologia , Animais , Modelos Animais de Doenças , Eritrócitos , Fibrose , Inflamação/terapia , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Masculino , Camundongos , Peptídeos , Interferência de RNA , RNA Interferente Pequeno/uso terapêutico , Traumatismo por Reperfusão/complicações , Fatores de Transcrição da Família Snail/metabolismo , Fator de Transcrição RelA/metabolismo , Obstrução Ureteral/complicações
20.
BMC Nephrol ; 22(1): 183, 2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-34011291

RESUMO

INTRODUCTION: Osteoporosis is one of the important bone abnormalities in chronic kidney disease-mineral and bone disorder (CKD-MBD) and still lacks a sensitive biomarker to diagnose. Fibroblast growth factor 21 (FGF21) can stimulate bone loss in patients with diabetes and increase in CKD patients. In this study, we investigated whether FGF21 could serve as a biomarker to predict osteoporosis in a haemodialysis cohort. METHODS: We recorded demographic information, biochemical data, and serum FGF21 and FGF23 levels and measured the CT attenuation values of 339 haemodialysis patients from two large medical centres. We assessed the correlation of CT attenuation values with serum FGF21 and FGF23 levels and tested whether they were independent factors for osteoporosis. ROC curves were constructed to compare the prognostic value of FGF21 and FGF23 for osteoporosis. RESULTS: Based on the CT attenuation value, serum FGF21 levels were higher in our osteoporosis group (median 640.86 pg/ml vs. 245.46 pg/ml, P ˂ 0.01). Meanwhile, FGF21 (r = -0.136, P < 0.05) and FGF23 (r = -0.151, P < 0.05) were both negatively associated with osteoporosis. Moreover, FGF21 (ß = -0.067, P < 0.05) was an independent factor for osteoporosis. Furthermore, FGF21 combined with age yielded a marked specificity (90.5 %) and sensitivity (61.8 %) in predicting osteoporosis of haemodialysis patients with less residual renal function. CONCLUSIONS: FGF21 has a positive relationship with the incidence of osteoporosis in patients on haemodialysis. FGF21 combined with age is a good predictive biomarker for osteoporosis in patients on haemodialysis, especially those with less residual renal function.


Assuntos
Fatores de Crescimento de Fibroblastos/sangue , Osteoporose/sangue , Insuficiência Renal Crônica/complicações , Idoso , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Incidência , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Osteoporose/complicações , Osteoporose/diagnóstico , Osteoporose/epidemiologia , Curva ROC , Diálise Renal , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/terapia , Coluna Vertebral/diagnóstico por imagem , Tomografia Computadorizada por Raios X
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