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1.
Int Immunopharmacol ; 107: 108637, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35279513

RESUMEN

Mitochondrial dysfunction and nonbacterial inflammation are common pathogenesis of acute kidney injury (AKI) and chronic kidney disease (CKD). However, the pathophysiology of kidney disease has not been completely elucidated. Mitochondria have their own DNA, namely mitochondria DNA (mtDNA), which encodes key proteins in the mitochondrial respiratory complex. Leakage of mtDNA into the cytoplasm can lead to inflammation and this process has been reported to be involved in the development of a variety of diseases. Here we discuss the structure and function of mtDNA, more specifically, to emphasize it leaks into the cytoplasm and inflammatory activation pathways. Finally, the role of mtDNA in kidney diseases is also summarized and provides a direction for future research.


Asunto(s)
Lesión Renal Aguda , Insuficiencia Renal Crónica , Lesión Renal Aguda/patología , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Femenino , Humanos , Inflamación/metabolismo , Riñón/patología , Masculino , Mitocondrias/metabolismo , Insuficiencia Renal Crónica/etiología
2.
Diabetes ; 71(5): 1034-1050, 2022 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-35133431

RESUMEN

Mitochondria-associated endoplasmic reticulum membrane (MAM) may have a role in tubular injury in diabetic nephropathy (DN), but the precise mechanism remains unclear. Here, we demonstrate that the expression of phosphofurin acidic cluster sorting protein 2 (PACS-2), a critical regulator of MAM formation, is significantly decreased in renal tubules of patients with DN, and PACS-2 expression is positively correlated with renal function and negatively correlated with degrees of tubulointerstitial lesions. Conditional deletion of Pacs-2 in proximal tubules (PTs) aggravates albuminuria and tubular injury in a streptozotocin-induced mouse model of diabetes. Mitochondrial fragmentation, MAM disruption, and defective mitophagy accompanied by altered expression of mitochondrial dynamics and mitophagic proteins, including Drp1 and Becn1, are observed in tubules of diabetic mice; these changes are more pronounced in PT-specific Pacs-2 knockout mice. In vitro, overexpression of PACS-2 in HK-2 cells alleviates excessive mitochondrial fission induced by high glucose concentrations through blocking mitochondrial recruitment of DRP1 and subsequently restores MAM integrity and enhances mitophagy. Mechanistically, PACS-2 binds to BECN1 and mediates the relocalization of BECN1 to MAM, where it promotes the formation of mitophagosome. Together, these data highlight an important but previously unrecognized role of PACS-2 in ameliorating tubular injury in DN by facilitating MAM formation and mitophagy.


Asunto(s)
Diabetes Mellitus Experimental , Nefropatías Diabéticas , Animales , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/metabolismo , Retículo Endoplásmico/metabolismo , Femenino , Humanos , Masculino , Ratones , Mitocondrias/metabolismo , Mitofagia
3.
Cell Death Dis ; 12(11): 1031, 2021 10 30.
Artículo en Inglés | MEDLINE | ID: mdl-34718329

RESUMEN

Autophagy-mediated lipotoxicity plays a critical role in the progression of diabetic nephropathy (DN), but the precise mechanism is not fully understood. Whether lipophagy, a selective type of autophagy participates in renal ectopic lipid deposition (ELD) and lipotoxicity in the kidney of DN is unknown. Here, decreased lipophagy, increased ELD and lipotoxcity were observed in tubular cells of patients with DN, which were accompanied with reduced expression of AdipoR1 and p-AMPK. Similar results were found in db/db mice, these changes were reversed by AdipoRon, an adiponectin receptor activator that promotes autophagy. Additionally, a significantly decreased level of lipophagy was observed in HK-2 cells, a human proximal tubular cell line treated with high glucose, which was consistent with increased lipid deposition, apoptosis and fibrosis, while were partially alleviated by AdipoRon. However, these effects were abolished by pretreatment with ULK1 inhibitor SBI-0206965, autophagy inhibitor chloroquine and enhanced by AMPK activator AICAR. These data suggested by the first time that autophagy-mediated lipophagy deficiency plays a critical role in the ELD and lipid-related renal injury of DN.


Asunto(s)
Autofagia , Nefropatías Diabéticas/patología , Túbulos Renales/patología , Metabolismo de los Lípidos , Proteínas Quinasas Activadas por AMP/metabolismo , Adulto , Animales , Apoptosis/efectos de los fármacos , Autofagosomas/efectos de los fármacos , Autofagosomas/metabolismo , Autofagia/efectos de los fármacos , Homólogo de la Proteína 1 Relacionada con la Autofagia/antagonistas & inhibidores , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Línea Celular , Activadores de Enzimas/farmacología , Femenino , Fibrosis , Ontología de Genes , Glucosa/toxicidad , Humanos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Túbulos Renales/efectos de los fármacos , Túbulos Renales/fisiopatología , Gotas Lipídicas/ultraestructura , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Proteínas Asociadas a Microtúbulos/metabolismo , Persona de Mediana Edad , Estrés Oxidativo/efectos de los fármacos , Fosforilación/efectos de los fármacos , Piperidinas/farmacología , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Proteínas de Unión a GTP rab7/metabolismo
4.
Front Physiol ; 12: 659751, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33995126

RESUMEN

NLRP3-mediated inflammation is closely related to the pathological progression of diabetic nephropathy (DN). DsbA-L, an antioxidant enzyme, plays a protective role in a variety of diseases by inhibiting ER stress and regulating metabolism. However, the relationship of DsbA-L with inflammation, especially the NLRP3 inflammasome, has not been examined. In this study, we note that activation of the NLRP3 inflammasome and exacerbated fibrosis were observed in the kidneys of diabetic DsbA-L-knockout mice and were accompanied by decreased phosphorylation of AMP-activated protein kinase (AMPK). Moreover, correlation analysis shows that the phosphorylation of AMPK was negatively correlated with NLRP3 expression and tubular damage. In addition, the decreased AMPK phosphorylation and NLRP3 activation induced by high glucose (HG) in HK-2 cells could be alleviated by the overexpression of DsbA-L. Interestingly, the protective effect of DsbA-L was eliminated after treatment with compound C, a well-known AMPK inhibitor. Our findings suggest that DsbA-L inhibits NLRP3 inflammasome activation by promoting the phosphorylation of AMPK.

5.
Clin Sci (Lond) ; 135(10): 1273-1288, 2021 05 28.
Artículo en Inglés | MEDLINE | ID: mdl-33997886

RESUMEN

Cisplatin (Cis) can cause chronic kidney disease (CKD) and promote renal fibrosis, but the underlying mechanism is not fully understood. Hypoxia inducible factor-1α (HIF-1α) can promote renal fibrosis in some kidney diseases, but its role in Cis-induced CKD is still unknown. Notch-1 is a recognized molecule that promotes renal fibrosis under pathological circumstances, and evidence shows that HIF-1α and Notch-1 are closely related to each other. In the present study, mice with HIF-1α gene knockout in proximal tubular cells (PTCs) (PT-HIF-1α-KO) were generated and treated with Cis to induce CKD. A human proximal tubular cell line (HK-2) and primary mouse PTCs were used for in vitro studies. The results showed that HIF-1α was increased in the kidneys of Cis-treated wild-type mice, accompanied by elevated Notch-1, Notch-1 intracellular domain (N1ICD), Hes-1 and renal fibrosis. However, these alterations were partially reversed in PT-HIF-1α-KO mice. Similar results were observed in HK-2 cells and primary mouse PTCs. In addition, treating the cells with Cis induced a marked interaction of HIF-1α and N1ICD. Further inhibiting Notch-1 significantly reduced cellular fibrogenesis but did not affect HIF-1α expression. The data suggested that HIF-1α could promote renal fibrosis in Cis-induced CKD by activating Notch-1 both transcriptionally and post-transcriptionally and that HIF-1α may serve as a potential therapeutic target for Cis-induced CKD.


Asunto(s)
Fibrosis/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/metabolismo , Animales , Células Epiteliales/metabolismo , Fibrosis/etiología , Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/deficiencia , Riñón/metabolismo , Túbulos Renales Proximales/patología
6.
Front Endocrinol (Lausanne) ; 12: 609580, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33679616

RESUMEN

Ectopic fat deposition (EFD) in the kidney plays a key role in the development of diabetic nephropathy (DN). Mitochondria-associated ER membranes (MAMs) are structures that connect to the endoplasmic reticulum (ER) and are involved in lipid metabolism. However, there are few studies on MAMs in the field of kidney disease, and the relationship between EFD and MAMs in DN is still unclear. In this study, increased EFD in the kidneys of DN patients was observed, and analysis showed that the degree of EFD was positively correlated with renal damage. Then, the MAMs were quantified by an in situ proximity ligation assay (PLA). The MAMs in the kidneys were found to gradually decrease through the different stages of DN, while the expression of ADRP (a marker of lipid droplets) and tubulointerstitial damage increased. Moreover, correlation analysis showed that the MAMs were negatively correlated with serum lipid levels, the EFD in the kidney and renal damage. Finally, we observed decreased expression of MAM-control proteins (DsbA-L, PACS-2, and MFN-2) in different stages of DN and they were associated with lipid deposition and renal damage. These data showed that the destruction of MAMs in DN might be the cause of EFD and interstitial damage in the kidney.


Asunto(s)
Tejido Adiposo , Coristoma/prevención & control , Nefropatías Diabéticas/patología , Enfermedades Renales/prevención & control , Lípidos/efectos adversos , Membranas Mitocondriales/fisiología , Adulto , Estudios de Casos y Controles , Coristoma/metabolismo , Nefropatías Diabéticas/metabolismo , Progresión de la Enfermedad , Retículo Endoplásmico/fisiología , Femenino , Humanos , Enfermedades Renales/etiología , Metabolismo de los Lípidos/fisiología , Masculino , Persona de Mediana Edad
7.
J Diabetes Investig ; 12(8): 1346-1358, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-33411406

RESUMEN

AIMS/INTRODUCTION: The aim of this study was to determine whether distinct subphenotypes of patients with type 2 diabetes in the European classification exist in Chinese populations, and to further establish novel subphenotypes more suitable for Chinese populations. MATERIAL AND METHODS: The research retrospectively analyzed 5414 patients with type 2 diabetes from the National Clinical Research Center for Metabolic Diseases Diabetes Center in China, and a two-step cluster analysis was carried out. First, we confirmed the European classification in Chinese populations by six parameters, including age at disease onset, body mass index, glycosylated hemoglobin, homeostatic model assessment 2 to estimate ß-cell function and insulin resistance, and glutamate decarboxylase antibodies. Furthermore, triglycerides and uric acid were added to refine the cluster analysis, and Cox regression was used to evaluate the risk of diabetic complications. RESULTS: Just three clusters were replicated in our cohort according to Emma Ahlqvist's European classification. When other variables were added to the cluster analysis, seven subgroups were identified, including five clusters of the European classification and two novel subgroups, namely, uric acid-related diabetes and inheritance-related diabetes. Compared with patients with inheritance-related diabetes, patients with severe insulin-resistant diabetes showed a higher risk of diabetic peripheral neuropathy, hypertension and chronic kidney disease, and the uric acid-related diabetes subgroup showed a higher risk of coronary heart disease, cerebral vascular disease and end-stage renal disease. Patients with severe insulin-deficient diabetes showed a higher risk of diabetic retinopathy and diabetic foot than those with inheritance-related diabetes. Furthermore, there were sex-specific associations between subgroups and clinical outcomes. No significant difference was observed in the prevalence of cancer in each subgroup. CONCLUSIONS: Seven subgroups of type 2 diabetes were identified in Chinese populations, with distinct characteristics and disparate clinical outcomes. This etiology-based stratification might contribute to the diagnosis and management of type 2 diabetes.


Asunto(s)
Diabetes Mellitus Tipo 2/clasificación , Adulto , Edad de Inicio , Anciano , Índice de Masa Corporal , China/epidemiología , Análisis por Conglomerados , Estudios de Cohortes , Complicaciones de la Diabetes/epidemiología , Complicaciones de la Diabetes/genética , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Femenino , Hemoglobina Glucada/análisis , Humanos , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , Neoplasias/epidemiología , Prevalencia , Estudios Retrospectivos , Resultado del Tratamiento , Ácido Úrico/metabolismo
8.
BMJ Open ; 11(1): e041072, 2021 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-33431489

RESUMEN

OBJECTIVE: To investigate the association between a parental and/or sibling history of diabetes and clinical characteristics. DESIGN: A cross-sectional study. SETTING: The data were collected from the endocrinology department of The Second Xiangya Hospital of Central South University from June 2017 to October 2019. PARTICIPANTS: A total of 894 newly diagnosed patients with type 2 diabetes were recruited. Data on clinical characteristics were collected from patient medical records. Pancreatic ß-cell function and insulin resistance were calculated with the homeostatic model assessment. SPSS V.25.0 was used to perform the analysis. RESULTS: The percentages of patients with parental and sibling histories of diabetes were 14.8% and 9.8%, respectively. The prevalence of diabetic ketoacidosis (DKA) was 3.9%. Compared with those with no parental history of diabetes, patients with a parental history of diabetes were characterised by early-onset disease (41.70±10.88 vs 51.17±14.09 years), poor glycaemic control of fasting blood glucose (10.84±5.21 vs 8.91±4.38 mmol/L) and a high prevalence of DKA (7.6% vs 3.3%). The patients with a sibling history of diabetes had later disease onset (56.05±9.86 vs 49.09±14.29 years) and lower BMI (24.49±3.48 vs 25.69±3.86 kg/m2) than those with no sibling history of diabetes. Univariate regression suggested that both parental history (p=0.037) and sibling history (p=0.011) of diabetes were associated with ß-cell function; however, multiple regression analysis showed that only a sibling history of diabetes was associated with ß-cell function (p=0.038). Univariate regression revealed a positive correlation between parental history of diabetes (p=0.023, OR=2.416, 95% CI 1.132 to 5.156) and DKA. Unfortunately, this correlation was not statistically significant for either patients with a parental history (p=0.234, OR=1.646, 95% CI 0.724 to 3.743) or those with a sibling history (p=0.104, OR=2.319, 95% CI 0.841 to 6.389) after adjustments for confounders. CONCLUSION: A sibling history of diabetes was associated with poor ß-cell function, and a parental history of diabetes was associated with poor glycaemic control and a high prevalence of DKA.


Asunto(s)
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Cetoacidosis Diabética , Glucemia , China/epidemiología , Estudios Transversales , Diabetes Mellitus Tipo 2/epidemiología , Cetoacidosis Diabética/epidemiología , Humanos
9.
Sci Rep ; 10(1): 17056, 2020 10 13.
Artículo en Inglés | MEDLINE | ID: mdl-33051498

RESUMEN

To investigate the relationship between diabetic foot complications (DFCs) and clinical characteristics, especially the number and types of first-degree family members with diabetes. A total of 8909 type 2 diabetes patients were enrolled. The clinical characteristics of these patients, including DFCs and family history of diabetes (FHD), were collected from medical records. Multiple regression was used to investigate the association between FHD and DFCs after adjusting for confounding factors. The patients with one and more than one first-degree family member with diabetes accounted for 18.7% and 12.8%, respectively. The proportions of the participants with a father with diabetes, a mother with diabetes, both parents with diabetes, siblings with diabetes, father and siblings with diabetes, mother and siblings with diabetes, and both parents and siblings with diabetes were 3.5%, 6.2%, 1.1%, 14.4%, 1.5%, 4%, and 0.7%, respectively. The multiple regression analysis showed that the number of family members with diabetes was positively associated with DFCs. However, among the different types of FHD, only the patients with a mother with diabetes showed a statistical association with DFCs. In addition to FHD, other factors, including gender, body mass index, platelet count, hemoglobin levels, albumin levels, high-density cholesterol levels, diabetic peripheral neuropathy, and the use of lipid-lowering agents, oral hypoglycemic agents, and insulin, were also associated with DFCs. DFCs were associated with different numbers of family members with diabetes and types of FHD. This association reveals the importance of genetic and environmental factors in DFCs and highlights the importance of adding FHD to public health strategies targeting detecting and preventing the disease.


Asunto(s)
Diabetes Mellitus Tipo 2/fisiopatología , Pie Diabético/epidemiología , Anamnesis/estadística & datos numéricos , Adulto , Anciano , Glucemia/análisis , Índice de Masa Corporal , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Pie Diabético/fisiopatología , Femenino , Humanos , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Masculino , Persona de Mediana Edad , Análisis de Regresión , Factores de Riesgo , Circunferencia de la Cintura
10.
Front Endocrinol (Lausanne) ; 11: 564738, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33042022

RESUMEN

Background: Vitamin D status has been linked to diabetes-related complications due to multiple extraskeletal effects. We aimed to investigate the association between vitamin D deficiency (VDD) and diabetic vascular complications, including diabetic retinopathy (DR), diabetic kidney disease (DKD), and diabetic foot ulcers (DFU). Methods: A total of 4,284 Chinese patients with type 2 diabetic mellitus (T2DM) were enrolled into the cross-sectional study. VDD was defined as serum 25-hydroxyvitamin D <50 nmol/L. Demographic data, physical measurements, laboratory measurements, comorbidities, and related medications were collected and analyzed by VDD status. Poisson regression with robust variance estimation and binary logistic regression were performed to explore the relationship between VDD and diabetic complications. Results: The prevalence of VDD, DR, DKD, DFU accounted to 71.7% (95% confidence intervals [CI]: 70.3-73.0%), 28.5% (95% CI: 27.2-29.9%), 28.2% (95% CI: 26.8-29.5%), and 5.7% (95% CI: 5.1-6.5%), respectively. The prevalence ratios (95% CI) for DR and DKD by VDD status, adjusted for demographics, physical measurements, laboratory measurements, related complications, and comorbidities, and medications, were 1.093 (0.983-1.215) and 1.041 (0.937-1.156), respectively. The odds ratio (95% CI) for DFU by VDD status was 1.656 (1.159-2.367) in the final adjusted model. Meanwhile, the prevalence of VDD was significantly higher in patients with DFU compared with patients without DFU. Conclusions: The present study firstly indicated that VDD was significantly associated with a higher prevalence of DFU among Chinese T2DM patients. The association between VDD status and DR or DKD was not significant when adjusting for all potential covariates. Vitamin D screening or supplementation may be beneficial to prevent DFU and improve the prognosis of T2DM patients.


Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Pie Diabético/sangre , Nefropatías Diabéticas/sangre , Retinopatía Diabética/sangre , Deficiencia de Vitamina D/sangre , Vitamina D/análogos & derivados , Adulto , Anciano , China/epidemiología , Estudios Transversales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Pie Diabético/tratamiento farmacológico , Pie Diabético/epidemiología , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/epidemiología , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vitamina D/sangre , Vitamina D/uso terapéutico , Deficiencia de Vitamina D/tratamiento farmacológico , Deficiencia de Vitamina D/epidemiología , Adulto Joven
11.
Cell Prolif ; 53(11): e12909, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32975326

RESUMEN

OBJECTIVES: In diabetic nephropathy (DN), hypoxia-inducible factor-1α (HIF-1α) activation in tubular cells plays an important protective role against kidney injury. The effects may occur via the target genes of HIF-1α, such as haem oxygenase-1 (HO-1), but the exact mechanisms are incompletely understood. MATERIALS AND METHODS: Mice with proximal tubule-specific knockout of HIF-1α (PT-HIF-1α-/- mice) were generated, and diabetes was induced in these mice by streptozotocin (STZ) injection. In addition, to mimic a hypoxic state, cobaltous chloride (CoCl2 ) was applied to HK-2 cells. RESULTS: Our study first verified that conditional knockout of HIF-1α worsened tubular injury in DN; additionally, aggravated kidney dysfunction, renal histopathological alterations, mitochondrial fragmentation, ROS accumulation and apoptosis were observed in diabetic PT-HIF-1α-/- mice. In vitro study showed that compared to control group, HK-2 cells cultured under hypoxic ambiance displayed increased mitochondrial fragmentation, ROS production, mitochondrial membrane potential loss and apoptosis. These increases were reversed by overexpression of HIF-1α or treatment with a HO-1 agonist. Importantly, cotreatment with a HIF-1α inhibitor and a HO-1 agonist rescued the HK-2 cells from the negative impacts of the HIF-1α inhibitor. CONCLUSIONS: These data revealed that HIF-1α exerted a protective effect against tubular injury in DN, which could be mediated via modulation of mitochondrial dynamics through HO-1 upregulation.


Asunto(s)
Nefropatías Diabéticas/patología , Hemo-Oxigenasa 1/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Túbulos Renales Proximales/patología , Dinámicas Mitocondriales , Animales , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/metabolismo , Eliminación de Gen , Técnicas de Inactivación de Genes , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Túbulos Renales Proximales/metabolismo , Masculino , Ratones , Mitocondrias/genética , Mitocondrias/metabolismo , Mitocondrias/patología
12.
Front Cell Dev Biol ; 8: 595, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32766245

RESUMEN

Autophagy is a process of intracellular self-recycling and degradation that plays an important role in maintaining cell homeostasis. However, the molecular mechanism of autophagy remains to be further studied. Mitochondria-associated endoplasmic reticulum membranes (MAMs) are the region of the ER that mediate communication between the ER and mitochondria. MAMs have been demonstrated to be involved in autophagy, Ca2+ transport and lipid metabolism. Here, we discuss the composition and function of MAMs, more specifically, to emphasize the role of MAMs in regulating autophagy. Finally, some key information that may be useful for future research is summarized.

13.
FASEB J ; 34(9): 12599-12614, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32706145

RESUMEN

Renal tubulointerstitial fibrosis (TIF) is a common pathological feature of aristolochic acid (AA) nephropathy (AAN). G2/M arrest of proximal tubular cells (PTCs) is implicated in renal fibrosis of AAN, but the upstream regulatory molecule remains unknown. Hypoxia inducible factor-1α (HIF-1α) promotes renal fibrosis in kidney disease, but the role of HIF-1α in AAN is unclear. Evidence shows that HIF-1α and p21, a known inducer of cellular G2/M arrest, are closely related to each other. To investigate the role of HIF-1α in renal fibrosis of AAN and its effects on p21 expression and PTCs G2/M arrest, mice with HIF-1α gene knockout PTCs (PT-HIF-1α-KO) were generated, and AAN was induced by AA. In vitro tests were conducted on the human PTCs line HK-2 and primary mouse PTCs. HIF-1α and p21 expression, fibrogenesis, and G2/M arrest of PTCs were determined. Results showed that HIF-1α was upregulated in the kidneys of wild-type (WT) AAN mice, accompanied by p21 upregulation, PTCs G2/M arrest and renal fibrosis, and these alterations were reversed in PT-HIF-1α-KO AAN mice. Similar results were observed in HK-2 cells and were further confirmed in primary PTCs from PT-HIF-1α-KO and WT mice. Inhibiting p21 in HK-2 cells and primary PTCs did not change the expression of HIF-1α, but G2/M arrest and fibrogenesis were reduced. These data indicate that HIF-1α plays a key role in renal fibrosis in AAN by inducing PTCs G2/M arrest modulated through p21. HIF-1α may serve as a potential therapeutic target for AAN.


Asunto(s)
Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Células Epiteliales/citología , Subunidad alfa del Factor 1 Inducible por Hipoxia/fisiología , Túbulos Renales Proximales , Nefritis Intersticial/metabolismo , Animales , Ácidos Aristolóquicos , Línea Celular , Fibrosis/inducido químicamente , Puntos de Control de la Fase G2 del Ciclo Celular , Humanos , Túbulos Renales Proximales/citología , Túbulos Renales Proximales/patología , Ratones , Ratones Noqueados
14.
Kidney Dis (Basel) ; 6(3): 195-203, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32523961

RESUMEN

OBJECTIVES: To investigate the characteristics of kidney stone disease (KSD) among the Chinese population with type 2 diabetes mellitus (T2DM) and identify sex-specific factors associated with KSD. METHODS: A single-center, cross-sectional analysis was performed among Chinese patients with T2DM. KSD was identified by ultrasonography or computed tomography results. Demographic data, physical measurements, laboratory measurements, comorbidities, and related medication data were collected and analyzed. Binary logistic regression was used to explore the associated factors. RESULTS: A total of 7,257 patients with T2DM were included in the study, of which 56.1% were male and 15.0% were diagnosed with KSD. The male-to-female ratio for KSD among T2DM patients was 1.35. Among all the T2DM patients, male gender, HOMA2-IR, uric acid, and renal cysts were independent risk factors for KSD development, whereas serum phosphorus and the use of angiotensin-converting enzyme inhibitors (ACEIs) were independent protective factors for KSD. Among male diabetic patients, triglycerides, HOMA2-IR, renal cysts, and urinary tract infections were all associated with a greater risk of KSD. In contrast, serum phosphorus was associated with a lower risk of KSD. Among female diabetic patients, systolic blood pressure and HOMA2-B were both contributing factors, and ACEIs acted as a protective factor for KSD. CONCLUSION: Among Chinese patients with T2DM, approximately 1 in 7 patients was affected by KSD, and the prevalence was twice as high as that in the general Chinese population. The factors associated with KSD varied by sex among T2DM patients. Focusing on these factors is beneficial for reducing the risk of KSD and delaying kidney damage in diabetic patients.

15.
Front Physiol ; 11: 616167, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33384617

RESUMEN

Introduction: Simple renal cysts (SRCs) are the most common acquired cystic kidney disease, but the relationship between SRCs and renal function has not been clarified in patients with type 2 diabetes mellitus (T2DM). Methods: A retrospective study was conducted to analyze the clinical features of renal cysts and ultrasound data of the kidney in 4,304 patients with T2DM. Results: The prevalence of SRCs in patients with T2DM was 21.1%. Compared to patients with no SRCs, patients with SRCs had worse renal function (estimated glomerular filtration rate: 108.65 ± 40.93 vs. 92.38 ± 42.1 ml/min/1.73 m2, p < 0.05). After adjusting the confounders, SRC was related to estimated glomerular filtration rate in patients with T2DM [odds ratio = 1.49, 95% confidence interval (1.24, 1.79), p < 0.01]. Age, gout, proteinuria, cerebrovascular disease (CVD), and increased serum phosphorus levels were associated with SRCs in patients with T2DM. Conclusion: SRCs are associated with worse renal function in patients with T2DM. More attention should be paid to gout, proteinuria, CVD, serum phosphorus levels, and renal function in T2DM patients with SRCs.

16.
J Diabetes ; 12(3): 237-246, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31602779

RESUMEN

BACKGROUND: We aim to design a scoring model for differential diagnosis between diabetic nephropathy (DN) and nondiabetic renal disease (NDRD) in type 2 diabetic patients through a combination of clinical variables. METHODS: A total of 170 patients with type 2 diabetes who underwent kidney biopsies were included and divided into three groups according to pathological findings: DN group (n = 46), MIX group (DN + NDRD, n = 54), NDRD group (n = 70). Clinical characteristics and laboratory data were collected and compared among groups. Variables with a significant statistical difference between DN and NDRD patients were analyzed by logistic regression to predict the presence of NDRD; then a scoring model was established based on the regression coefficient and further validated in an independent cohort of 67 patients prospectively. RESULTS: On biopsy, 72.9% of patients had NDRD, and the most common pathological type was membranous nephropathy. The established scoring model for predicting NDRD included five predictors: age, systolic blood pressure, hemoglobin, duration of diabetes, and absence of diabetic retinopathy. The model demonstrated good discrimination and calibration (area under curve [AUC] 0.863, 95% CI, 0.800-0.925; Hosmer-Lemeshow [H-L] P = .062). Furthermore, high prediction accuracy (AUC = 0.900; 95% CI, 0.815-0.985) in the validation cohort proved the stability of the model. CONCLUSIONS: We present a simple, robust scoring model for predicting the presence of NDRD with high accuracy (0.85) for the first time. This decision support tool provides a noninvasive method for differential diagnosis of DN and NDRD, which may help clinicians assess the risk-benefit ratio of kidney biopsy for type 2 diabetic patients with renal impairment.


Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/diagnóstico , Retinopatía Diabética/diagnóstico , Enfermedades Renales/diagnóstico , Adulto , Anciano , Biopsia , Nefropatías Diabéticas/etiología , Retinopatía Diabética/etiología , Diagnóstico Diferencial , Femenino , Humanos , Riñón/metabolismo , Riñón/patología , Riñón/ultraestructura , Enfermedades Renales/complicaciones , Enfermedades Renales/patología , Modelos Logísticos , Masculino , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Proyectos de Investigación , Estudios Retrospectivos , Sensibilidad y Especificidad , Adulto Joven
19.
Kidney Int ; 95(4): 880-895, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30791996

RESUMEN

Ectopic fat deposition (EFD) in the kidney has been shown to play a causal role in diabetic nephropathy; however, the mechanism underlying EFD remains elusive. By transcriptome analysis, we found decreased expression levels of disulfide-bond A oxidoreductase-like protein (DsbA-L) in the kidneys of diabetic mice (induced by high-fat diet plus Streptozotocin) compared with control mice. Increased expression of adipocyte differentiation-related protein and abnormal levels of collagen I, fibronectin, and phosphorylated 5'AMP-activated kinase (p-AMPK), adipose triglyceride lipase (p-ATGL), and HMG-CoA reductase (p-HMGCR) were also observed in diabetic mice. These alterations were accompanied by deposition of lipid droplets in the kidney, and were more pronounced in diabetic DsbA-L knockout mice. In vitro, overexpression of DsbA-L ameliorated high glucose-induced intracellular lipid droplet deposition in a human proximal tubular cell line, and DsbA-L siRNA aggravated lipid droplet deposition and reduced the levels of p-AMPK, p-ATGL, and p-HMGCR. High glucose and palmitic acid treatment enhanced the expression of interleukin-1ß and interleukin-18; these enhancements were further increased after treatment with DsbA-L siRNA but alleviated by co-treatment with an AMPK activator. In kidney biopsy tissue from patients with diabetic nephropathy, DsbA-L expression was negatively correlated with EFD and tubular damage. Collectively, these results suggest that DsbA-L has a protective role against EFD and lipid-related kidney damage in diabetic nephropathy. Activation of the AMPK pathway is a potential mechanism underlying DsbA-L action in the kidney.


Asunto(s)
Nefropatías Diabéticas/patología , Glutatión Transferasa/metabolismo , Riñón/patología , Metabolismo de los Lípidos , Adenilato Quinasa/metabolismo , Adulto , Animales , Biopsia , Línea Celular , Colesterol/biosíntesis , Diabetes Mellitus Experimental/etiología , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/metabolismo , Dieta Alta en Grasa/efectos adversos , Femenino , Glutatión Transferasa/genética , Humanos , Hidroximetilglutaril-CoA Reductasas/metabolismo , Riñón/citología , Gotas Lipídicas/patología , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , ARN Interferente Pequeño/metabolismo , Estreptozocina/toxicidad
20.
Kidney Dis (Basel) ; 4(4): 226-237, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30574499

RESUMEN

BACKGROUND: Diabetes mellitus (DM) poses a severe threat to global public health. Diabetic nephropathy (DN) is one of the most common complications of diabetes and the leading cause of end-stage renal disease (ESRD). Approximately 30-40% of DM patients in the world progress to ESRD, which emphasizes the effect of genetic factors on DN. Family clustering also supports the important role of hereditary factors in DN and ESRD. Therefore, a large number of genetic studies have been carried out to identify susceptibility genes in different diabetic cohorts. Extensive susceptibility genes of DN and ESRD have not been identified until recently. SUMMARY AND KEY MESSAGES: Some of these associated genes function as pivotal regulators in the pathogenesis of DN, such as those related to glycometabolism and lipid metabolism. However, the functions of most of these genes remain unclear. In this article, we review several susceptibility genes according to their genetic functions to make it easier to determine their exact effect on DN and to provide a better understanding of the advancements from genetic studies. However, several challenges associated with investigating the genetic factors of DN still exist. For instance, it is difficult to determine whether these variants affect the expression of the protein they encode or other cytokines. More efforts should be made to determine how these genes influence the progression of DN. In addition, many results could not be replicated among races, suggesting that the association between genetic polymorphisms and DN is race-specific. Therefore, large, well-designed studies involving more relevant variables and ethnic groups and more relevant functional studies are urgently needed. These studies may be beneficial and retard the progression of DN by early intervention, especially for patients who carry certain risk alleles or genotypes.

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