Diabetic kidney disease(DKD)represents a significant challenge for diabetes management and public health as it affects the quality of life and metabolic control of millions of people around the world.Characterized by ...Diabetic kidney disease(DKD)represents a significant challenge for diabetes management and public health as it affects the quality of life and metabolic control of millions of people around the world.Characterized by persistent albuminuria and impaired renal function,DKD is an insidious consequence of chronic hyperglycemia and has far-reaching implications for cardiovascular health and mortality.More and more researchers in this field are focusing on the identification of reliable urinary biomarkers that can serve as early indicators of kidney disease progression and enable timely intervention through tailored therapeutic strategies.These biomarkers offer a potential way to improve the diagnosis,monitoring and understanding of kidney disease associated with diabetes,a persistent global health problem.Different types of urinary biomarkers provide insight into the pathophysiological processes involved in DKD.Albumin,for instance,is a crucial biomarker that signals microalbuminuria even before kidney function declines.Other promising candidates include several proteins,such as kidney injury molecule-1,which clearly indicates tubular damage to the kidneys,and neutrophil gelatinase-associated lipocalin,a marker of severe acute kidney injury.In addition,innovations in metabolomics have led to the discovery of certain specific metabolic signatures.These signatures can help distinguish DKD from other forms of kidney disease and show a certain complexity and interconnectivity in overall renal pathology.Finally,the role of many genetic and epigenetic factors is being investigated,highlighting how urinary biomarkers may reflect not only extreme injury but also an individual’s genetic predisposition to renal complications.As they become better understood,urinary biomarkers have the potential to significantly improve outcomes and risk stratification for people with DKD.Incorporating biomarker data into routine clinical practice could improve the ability to detect the disease earlier,monitor disease progression more effectively and personalize treatment methods.Moreover,elucidating the mechanisms behind these biomarkers could inspire new treatment approaches that focus on the underlying causes of DKD rather than just treating the symptoms.This will lead to better patient care and improved outcomes for this at-risk group.展开更多
Objective This study aimed to investigate the associations of the triglyceride-glucose(TyG)index with kidney function decline,cardiovascular disease(CVD)events,and all-cause mortality across different glucose toleranc...Objective This study aimed to investigate the associations of the triglyceride-glucose(TyG)index with kidney function decline,cardiovascular disease(CVD)events,and all-cause mortality across different glucose tolerance statuses.Methods We analyzed 8,434 participants from the China Cardiometabolic Disease and Cancer Cohort(4C)Study.The primary outcomes were kidney function decline,CVD events,and all-cause mortality.Associations between the TyG index and outcomes were evaluated using binary logistic regression models.Results During a 5-year follow-up,150 participants(1.80%)developed kidney function decline,357(4.30%)experienced CVD events,and 335(4.00%)died from all causes.An elevated TyG index was associated with increased risks of kidney function decline,nonfatal CVD events,and all-cause mortality in the overall population and among participants with diabetes(quartile 4[Q4]vs.quartile 1[Q1]:hazard ratio[HR][95%confidence interval,P-value]=4.97[1.41-31.71,P=0.034],4.63[1.25-30.19,P=0.047],and 4.54[1.70-15.88,P=0.007],respectively).These associations were not statistically significant in participants with normal glucose tolerance or prediabetes.Notably,an elevated TyG index was significantly associated with increased risk of fatal CVD events in the overall population and across all glucose tolerance subgroups,with the strongest association observed in participants with prediabetes rather than diabetes.Conclusions The TyG index is significantly associated with the risks of kidney function decline,CVD events,and all-cause mortality,and these associations differ by glucose tolerance status.展开更多
Diabetic kidney disease(DKD)is a major complication of diabetes mellitus,driven by hyperglycemia-induced oxidative stress,ER stress,and mitochondrial apoptosis.This study examined the protective effects of Morin again...Diabetic kidney disease(DKD)is a major complication of diabetes mellitus,driven by hyperglycemia-induced oxidative stress,ER stress,and mitochondrial apoptosis.This study examined the protective effects of Morin against hyperglycemia-induced renal tubular injury,alone or in combination with the SGLT2 inhibitor Empagliflozin,with emphasis on the ATF6-DAPK1 axis.HK2 cells were exposed to high glucose with or without Morin and/or Empagliflozin.Cellular stress,mitochondrial function,and apoptosis were assessed.Morin-DAPK1 binding was examined via molecular docking,surface plasmon resonance(SPR),and cell thermal shift assay(CETSA).db/db mice received vehicle,Empagliflozin,Morin,or their combination for 14 weeks,followed by renal histological,biochemical,and metabolic evaluations.Morin reduced ROS accumulation,ER stress(p-PERK,p-eIF2α,CHOP,cleaved ATF6),mitochondrial dysfunction,and apoptosis in HK2 cells.It suppressed DAPK1 mRNA expression via ATF6 inhibition and directly bound DAPK1(Kd=1.61μmol·L−1),disrupting its interaction with pro-apoptotic BAK/BIK.Empagliflozin indirectly downregulated DAPK1 through ER stress relief.Combination therapy synergistically reduced oxidative stress,preserved mitochondrial membrane potential,and prevented apoptosis.In db/db mice,both compounds improved renal structure,lowered blood glucose,reduced UACR,and inhibited kidney stress markers,with greater improvements in the combination group,which also alleviated hepatic steatosis.Morin exhibits renoprotective effects against high glucose-induced cellular stress and diabetic kidney disease,at least partially via DAPK1 targeting.Co-administration with Empagliflozin enhances these effects,supporting its potential as an adjunct therapy for hyperglycemia-induced kidney injury.展开更多
摘要Diabetic kidney disease(DKD)represents a significant challenge for diabetes management and public health as it affects the quality of life and metabolic control of millions of people around the world.Characterized by persistent albuminuria and impaired renal function,DKD is an insidious consequence of chronic hyperglycemia and has far-reaching implications for cardiovascular health and mortality.More and more researchers in this field are focusing on the identification of reliable urinary biomarkers that can serve as early indicators of kidney disease progression and enable timely intervention through tailored therapeutic strategies.These biomarkers offer a potential way to improve the diagnosis,monitoring and understanding of kidney disease associated with diabetes,a persistent global health problem.Different types of urinary biomarkers provide insight into the pathophysiological processes involved in DKD.Albumin,for instance,is a crucial biomarker that signals microalbuminuria even before kidney function declines.Other promising candidates include several proteins,such as kidney injury molecule-1,which clearly indicates tubular damage to the kidneys,and neutrophil gelatinase-associated lipocalin,a marker of severe acute kidney injury.In addition,innovations in metabolomics have led to the discovery of certain specific metabolic signatures.These signatures can help distinguish DKD from other forms of kidney disease and show a certain complexity and interconnectivity in overall renal pathology.Finally,the role of many genetic and epigenetic factors is being investigated,highlighting how urinary biomarkers may reflect not only extreme injury but also an individual’s genetic predisposition to renal complications.As they become better understood,urinary biomarkers have the potential to significantly improve outcomes and risk stratification for people with DKD.Incorporating biomarker data into routine clinical practice could improve the ability to detect the disease earlier,monitor disease progression more effectively and personalize treatment methods.Moreover,elucidating the mechanisms behind these biomarkers could inspire new treatment approaches that focus on the underlying causes of DKD rather than just treating the symptoms.This will lead to better patient care and improved outcomes for this at-risk group.
基金supported by the National Natural Science Foundation of China(Nos.82470907,82270880).
摘要Objective This study aimed to investigate the associations of the triglyceride-glucose(TyG)index with kidney function decline,cardiovascular disease(CVD)events,and all-cause mortality across different glucose tolerance statuses.Methods We analyzed 8,434 participants from the China Cardiometabolic Disease and Cancer Cohort(4C)Study.The primary outcomes were kidney function decline,CVD events,and all-cause mortality.Associations between the TyG index and outcomes were evaluated using binary logistic regression models.Results During a 5-year follow-up,150 participants(1.80%)developed kidney function decline,357(4.30%)experienced CVD events,and 335(4.00%)died from all causes.An elevated TyG index was associated with increased risks of kidney function decline,nonfatal CVD events,and all-cause mortality in the overall population and among participants with diabetes(quartile 4[Q4]vs.quartile 1[Q1]:hazard ratio[HR][95%confidence interval,P-value]=4.97[1.41-31.71,P=0.034],4.63[1.25-30.19,P=0.047],and 4.54[1.70-15.88,P=0.007],respectively).These associations were not statistically significant in participants with normal glucose tolerance or prediabetes.Notably,an elevated TyG index was significantly associated with increased risk of fatal CVD events in the overall population and across all glucose tolerance subgroups,with the strongest association observed in participants with prediabetes rather than diabetes.Conclusions The TyG index is significantly associated with the risks of kidney function decline,CVD events,and all-cause mortality,and these associations differ by glucose tolerance status.
基金supported by the Natural Science Foundation of China(No.U22A20286).
摘要Diabetic kidney disease(DKD)is a major complication of diabetes mellitus,driven by hyperglycemia-induced oxidative stress,ER stress,and mitochondrial apoptosis.This study examined the protective effects of Morin against hyperglycemia-induced renal tubular injury,alone or in combination with the SGLT2 inhibitor Empagliflozin,with emphasis on the ATF6-DAPK1 axis.HK2 cells were exposed to high glucose with or without Morin and/or Empagliflozin.Cellular stress,mitochondrial function,and apoptosis were assessed.Morin-DAPK1 binding was examined via molecular docking,surface plasmon resonance(SPR),and cell thermal shift assay(CETSA).db/db mice received vehicle,Empagliflozin,Morin,or their combination for 14 weeks,followed by renal histological,biochemical,and metabolic evaluations.Morin reduced ROS accumulation,ER stress(p-PERK,p-eIF2α,CHOP,cleaved ATF6),mitochondrial dysfunction,and apoptosis in HK2 cells.It suppressed DAPK1 mRNA expression via ATF6 inhibition and directly bound DAPK1(Kd=1.61μmol·L−1),disrupting its interaction with pro-apoptotic BAK/BIK.Empagliflozin indirectly downregulated DAPK1 through ER stress relief.Combination therapy synergistically reduced oxidative stress,preserved mitochondrial membrane potential,and prevented apoptosis.In db/db mice,both compounds improved renal structure,lowered blood glucose,reduced UACR,and inhibited kidney stress markers,with greater improvements in the combination group,which also alleviated hepatic steatosis.Morin exhibits renoprotective effects against high glucose-induced cellular stress and diabetic kidney disease,at least partially via DAPK1 targeting.Co-administration with Empagliflozin enhances these effects,supporting its potential as an adjunct therapy for hyperglycemia-induced kidney injury.