Urine extracellular vesicles capture kidney transcriptome and hyperglycemia linked mRNA signatures for type 1 diabetic kidney disease

Diabetic kidney disease (DKD) is a severe complication of type 1 diabetes (T1D), which lacks non-invasive early biomarkers. Although less explored, mRNAs in urinary extracellular vesicles (uEV) could reflect changes in the kidney transcriptome during DKD development. We performed genome-wide mRNA sequencing of >100 uEV samples from two T1D cohorts with 24-hour and overnight urine collections. Our uEV pipeline allowed reproducible detection of >10,000 mRNAs bearing overall similarity to kidney transcriptome. uEV from T1D DKD groups showed significant upregulation of 13 genes, prevalently expressed by proximal tubular cells within the kidney. Strikingly, six genes involved in cellular stress responses including protection against oxidative stress (GPX3, NOX4, MSRB, MSRA, HRSP12 and CRYAB) correlated with hyperglycemia and long-term changes in kidney function independent of albuminuria status. The study identified genes associated with glycemic stress in T1D DKD and confirmed the utility of uEV in capturing pathological gene expression signatures from kidney.

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Urinary Extracellular Vesicles as a Source of NGAL for Diabetic Kidney Disease Evaluation in Children and Adolescents With Type 1 Diabetes Mellitus

Frontiers in Endocrinology ◽

10.3389/fendo.2021.654269 ◽

2022 ◽

Vol 12 ◽

Author(s):

Francisca Ugarte ◽

Daniela Santapau ◽

Vivian Gallardo ◽

Carolina Garfias ◽

Anahí Yizmeyián ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Kidney Disease ◽

Type 1 Diabetes Mellitus ◽

Extracellular Vesicles ◽

Diabetic Kidney Disease ◽

Tubular Damage ◽

Activated T Cells ◽

Diabetic Kidney

BackgroundTubular damage has a role in Diabetic Kidney Disease (DKD). We evaluated the early tubulointerstitial damage biomarkers in type-1 Diabetes Mellitus (T1DM) pediatric participants and studied the correlation with classical DKD parameters.MethodsThirty-four T1DM and fifteen healthy participants were enrolled. Clinical and biochemical parameters [Glomerular filtration Rate (GFR), microalbuminuria (MAU), albumin/creatinine ratio (ACR), and glycated hemoglobin A1c (HbA1c)] were evaluated. Neutrophil gelatinase-associated lipocalin (NGAL), Hypoxia-inducible Factor-1α (HIF-1α), and Nuclear Factor of Activated T-cells-5 (NFAT5) levels were studied in the supernatant (S) and the exosome-like extracellular vesicles (E) fraction from urine samples.ResultsIn the T1DM, 12% had MAU >20 mg/L, 6% ACR >30 mg/g, and 88% had eGFR >140 ml/min/1.72 m2. NGAL in the S (NGAL-S) or E (NGAL-E) fraction was not detectable in the control. The NGAL-E was more frequent (p = 0.040) and higher (p = 0.002) than NGAL-S in T1DM. The T1DM participants with positive NGAL had higher age (p = 0.03), T1DM evolution (p = 0.03), and serum creatinine (p = 0.003) than negative NGAL. The NGAL-E correlated positively with tanner stage (p = 0.0036), the median levels of HbA1c before enrollment (p = 0.045) and was independent of ACR, MAU, and HbA1c at the enrollment. NFAT5 and HIF-1α levels were not detectable in T1DM or control.ConclusionUrinary exosome-like extracellular vesicles could be a new source of early detection of tubular injury biomarkers of DKD in T1DM patients.

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Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen

Journal of the American Society of Nephrology ◽

10.1681/asn.2019030218 ◽

2019 ◽

Vol 30 (10) ◽

pp. 2000-2016 ◽

Cited By ~ 29

Author(s):

Rany M. Salem ◽

Jennifer N. Todd ◽

Niina Sandholm ◽

Joanne B. Cole ◽

Wei-Min Chen ◽

...

Keyword(s):

Type 1 Diabetes ◽

Kidney Disease ◽

Basement Membrane ◽

Glomerular Basement Membrane ◽

Diabetic Kidney Disease ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Diabetic Kidney ◽

Genome Wide

BackgroundAlthough diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.MethodsTo identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function.ResultsOur GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1).ConclusionsThe 16 diabetic kidney disease–associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.

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Metabolic Changes and Oxidative Stress in Diabetic Kidney Disease

Antioxidants ◽

10.3390/antiox10071143 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1143

Author(s):

Midori Sakashita ◽

Tetsuhiro Tanaka ◽

Reiko Inagi

Keyword(s):

Oxidative Stress ◽

Kidney Disease ◽

Stress Responses ◽

Diabetic Kidney Disease ◽

Renin Angiotensin System ◽

Therapeutic Agents ◽

Metabolic Changes ◽

Diabetic Kidney ◽

Glucose Levels ◽

Patients With Diabetes

Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease, and it is crucial to understand the pathophysiology of DKD. The control of blood glucose levels by various glucose-lowering drugs, the common use of inhibitors of the renin–angiotensin system, and the aging of patients with diabetes can alter the disease course of DKD. Moreover, metabolic changes and associated atherosclerosis play a major role in the etiology of DKD. The pathophysiology of DKD is largely attributed to the disruption of various cellular stress responses due to metabolic changes, especially an increase in oxidative stress. Therefore, many antioxidants have been studied as therapeutic agents. Recently, it has been found that NRF2, a master regulator of oxidative stress, plays a major role in the pathogenesis of DKD and bardoxolone methyl, an activator of NRF2, has attracted attention as a drug that increases the estimated glomerular filtration rate in patients with DKD. This review outlines the altered stress responses of cellular organelles in DKD, their involvement in the pathogenesis of DKD, and discusses strategies for developing therapeutic agents, especially bardoxolone methyl.

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Vasopressin associated with renal vascular resistance in adults with longstanding type 1 diabetes with and without diabetic kidney disease

Journal of Diabetes and its Complications ◽

10.1016/j.jdiacomp.2020.107807 ◽

2020 ◽

pp. 107807

Author(s):

Federica Piani ◽

Trenton Reinicke ◽

Yuliya Lytvyn ◽

Isabella Melena ◽

Leif E. Lovblom ◽

...

Keyword(s):

Type 1 Diabetes ◽

Kidney Disease ◽

Vascular Resistance ◽

Diabetic Kidney Disease ◽

Renal Vascular Resistance ◽

Diabetic Kidney ◽

Renal Vascular

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Urinary Extracellular Vesicles for Diabetic Kidney Disease Diagnosis

Journal of Clinical Medicine ◽

10.3390/jcm10102046 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2046

Author(s):

Goren Saenz-Pipaon ◽

Saioa Echeverria ◽

Josune Orbe ◽

Carmen Roncal

Keyword(s):

Kidney Disease ◽

Extracellular Vesicles ◽

Diabetic Kidney Disease ◽

Current Knowledge ◽

Developed Countries ◽

Disease Diagnosis ◽

Renal Diseases ◽

Diabetic Kidney ◽

Glucose Levels ◽

Stage Renal Disease

Diabetic kidney disease (DKD) is the leading cause of end stage renal disease (ESRD) in developed countries, affecting more than 40% of diabetes mellitus (DM) patients. DKD pathogenesis is multifactorial leading to a clinical presentation characterized by proteinuria, hypertension, and a gradual reduction in kidney function, accompanied by a high incidence of cardiovascular (CV) events and mortality. Unlike other diabetes-related complications, DKD prevalence has failed to decline over the past 30 years, becoming a growing socioeconomic burden. Treatments controlling glucose levels, albuminuria and blood pressure may slow down DKD evolution and reduce CV events, but are not able to completely halt its progression. Moreover, one in five patients with diabetes develop DKD in the absence of albuminuria, and in others nephropathy goes unrecognized at the time of diagnosis, urging to find novel noninvasive and more precise early diagnosis and prognosis biomarkers and therapeutic targets for these patient subgroups. Extracellular vesicles (EVs), especially urinary (u)EVs, have emerged as an alternative for this purpose, as changes in their numbers and composition have been reported in clinical conditions involving DM and renal diseases. In this review, we will summarize the current knowledge on the role of (u)EVs in DKD.

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