Protective factors in diabetic kidney disease in patients with type 1 diabetes

1型糖尿病患者糖尿病肾病的保护因素

• 批准号: 10323271
• 负责人: Maria Luiza A Caramori
• 金额: $ 55.69万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-05 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323271
• 关键词: Advanced Glycosylation End Products; Area; Attenuated; Base Excision Repairs; Basic Science; Behavior; Biological Assay; Biological Markers; Biological Models; Candidate Disease Gene; Cell Cycle; Cells; Chronic; Collaborations; Complications of Diabetes Mellitus; DNA; DNA Damage; DNA Methylation; DNA Repair; DNA Repair Gene; DNA Repair Pathway; DNA biosynthesis; Data; Deoxyguanosine; Development; Diabetes Mellitus; Diabetic Nephropathy; Electrospray Ionization; End stage renal failure; Epigenetic Process; Epithelial Cells; Exhibits; Exposure to; Fibroblasts; Functional disorder; Gene Expression; Gene Expression Regulation; Genes; Genetic; Glucose; Histones; Hour; Human; Hyperglycemia; In Vitro; Individual; Inductively Coupled Plasma Mass Spectrometry; Injury; Insulin-Dependent Diabetes Mellitus; Investigation; Knowledge; Laboratories; Lead; Lesion; Link; Liquid Chromatography; Measures; Methodology; Methylation; Monozygotic twins; Oxidative Stress; Paper; Pathway interactions; Patients; Positioning Attribute; Post-Translational Protein Processing; Process; Proteins; Recovery; Regulation; Renal function; Research; Rodent Model; Role; Skin; Stress; Testing; Therapeutic; Therapeutic Agents; Tubular formation; Twin Multiple Birth; Up-Regulation; Urine; Variant; Work; adduct; cell behavior; cell injury; comparative; differential expression; disorder control; disorder prevention; disorder risk; healing; improved; improved outcome; in vivo; innovation; insight; kidney biopsy; non-diabetic; novel; outcome prediction; overexpression; oxidative DNA damage; oxidative damage; prevent; promoter; protective factors; protein expression; pyrosequencing; repaired; response; riboside; tandem mass spectrometry; urinary; volunteer

Scientific Abstract: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. While DKD injury factors are extensively studied, protective factors remain poorly defined and present a critical knowledge gap. Recently we and others described the existence of potential protective and healing mechanisms in DKD. These concepts warrant further investigation and have the potential to greatly improve outcomes. Papers from our and other laboratories confirm that after multiple passages cultured skin fibroblasts (SF) behaviors differ between patients with versus without DKD. Consistent with protective mechanisms, our earlier gene expression studies showed that individuals protected from DKD had some SF behaviors that differ both from patients with DKD and from normal controls, suggesting the protected group had unique cellular behaviors associated with very slow development of DKD lesions. Our recent gene expression studies (hi-seq) in SF grown in high glucose (HG) uncovered that pathways related to DNA replication and repair, protein repair, and cell cycle were markedly overexpressed in patients with type 1 diabetes (T1D) without DKD as compared to T1D patients with DKD and non-diabetic controls. These pathways were also differently expressed in SF of monozygotic twins discordant for T1D. Thus, upregulation of these pathways is posited as protective of DKD and epigenetically regulated. Hyperglycemia induces DNA damage, thus activating DNA repair pathways [primarily the base excision repair (BER) pathway] in order to restore DNA integrity and prevent cellular dysfunction. Indeed, the BER pathway was markedly up-regulated in T1D patients without DKD (p=5.14e-5) as compared to patients with DKD and controls. Our preliminary data indicate that BER pathway is also upregulated in proximal tubular epithelial cells (PTEC). We will test whether these pathway differences are associated with functional differences in SF and PTEC cultured from research skin and kidney biopsies in T1D volunteers. Our Specific Aims are to determine 1) changes in BER protein levels, DNA damage and repair capacity in SF in response to in vitro HG and their relationship to DKD risk, 2) changes in BER protein levels, DNA damage, repair capacity and response to a therapeutic agent in PTEC cultured in HG and their relationship to DKD risk, 3) urinary levels of DNA damage products in relation to DKD risk, and 4) epigenetic mechanisms associated with gene expression in key differentially expressed BER pathway genes. We hypothesize that, although both T1D patients with and without DKD may have increased BER pathway activity compared to controls, this activity will be much greater in the patients protected from DKD, and that our robust SF findings will be recapitulated in PTEC. Given the depth of our basic science strengths in the relevant areas, the unique research materials, the innovative technical capabilities of our superb investigative team, and our proven collaboration track, we are extremely well positioned for the successful completion of these studies. If our hypotheses are borne out, this work will open new research avenues aimed at DKD prevention.

科学摘要：糖尿病肾病（DKD）是终末期肾脏疾病的主要原因。虽然DKD