Eiichiro Satake1,2, Pierre-Jean Saulnier3,4, Hiroki Kobayashi1,2, Manoj K Gupta1,2, Helen C Looker3, Jonathan M Wilson5, Zaipul I Md Dom1,2, Katsuhito Ihara1,2, Kristina O'Neil1,2, Bozena Krolewski1,2, Caterina Pipino1,2,6, Meda E Pavkov7, Viji Nair8, Markus Bitzer8, Monika A Niewczas1,2, Matthias Kretzler8, Michael Mauer9, Alessandro Doria1,2, Behzad Najafian10, Rohit N Kulkarni1,2, Kevin L Duffin5, Marcus G Pezzolesi1,2,11, C Ronald Kahn1,2, Robert G Nelson12, Andrzej S Krolewski1,2. 1. Research Division, Joslin Diabetes Center, Boston, Massachusetts. 2. Department of Medicine, Harvard Medical School, Boston, Massachusetts. 3. Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona. 4. Poitiers University Hospital, University of Poitiers, Institut National de la Santé et de la Recherche Médicale (INSERM), Clinical Investigation Center CIC1402, Poitiers, France. 5. Diabetes and Complication Department, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana. 6. Department of Medical, Oral and Biotechnological Sciences, Center for Advanced Studies and Technology (CAST), University G. d'Annunzio, Chieti, Italy. 7. Division of Diabetes Translation, Centers for Disease Control and Prevention, Atlanta, Georgia. 8. Nephrology/Internal Medicine and Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan. 9. Department of Pediatrics and Medicine, University of Minnesota, Minneapolis, Minnesota. 10. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington. 11. Division of Nephrology and Hypertension, University of Utah, Salt Lake City, Utah. 12. Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona rnelson@phx.niddk.nih.gov.
Abstract
BACKGROUND: Mechanisms underlying the pro gression of diabetic kidney disease to ESKD are not fully understood. METHODS: We performed global microRNA (miRNA) analysis on plasma from two cohorts consisting of 375 individuals with type 1 and type 2 diabetes with late diabetic kidney disease, and targeted proteomics analysis on plasma from four cohorts consisting of 746 individuals with late and early diabetic kidney disease. We examined structural lesions in kidney biopsy specimens from the 105 individuals with early diabetic kidney disease. Human umbilical vein endothelial cells were used to assess the effects of miRNA mimics or inhibitors on regulation of candidate proteins. RESULTS: In the late diabetic kidney disease cohorts, we identified 17 circulating miRNAs, represented by four exemplars (miR-1287-5p, miR-197-5p, miR-339-5p, and miR-328-3p), that were strongly associated with 10-year risk of ESKD. These miRNAs targeted proteins in the axon guidance pathway. Circulating levels of six of these proteins-most notably, EFNA4 and EPHA2-were strongly associated with 10-year risk of ESKD in all cohorts. Furthermore, circulating levels of these proteins correlated with severity of structural lesions in kidney biopsy specimens. In contrast, expression levels of genes encoding these proteins had no apparent effects on the lesions. In in vitro experiments, mimics of miR-1287-5p and miR-197-5p and inhibitors of miR-339-5p and miR-328-3p upregulated concentrations of EPHA2 in either cell lysate, supernatant, or both. CONCLUSIONS: This study reveals novel mechanisms involved in progression to ESKD and points to the importance of systemic factors in the development of diabetic kidney disease. Some circulating miRNAs and axon guidance pathway proteins represent potential targets for new therapies to prevent and treat this condition.
BACKGROUND: Mechanisms underlying the pro gression of diabetic kidney disease to ESKD are not fully understood. METHODS: We performed global microRNA (miRNA) analysis on plasma from two cohorts consisting of 375 individuals with type 1 and type 2 diabetes with late diabetic kidney disease, and targeted proteomics analysis on plasma from four cohorts consisting of 746 individuals with late and early diabetic kidney disease. We examined structural lesions in kidney biopsy specimens from the 105 individuals with early diabetic kidney disease. Human umbilical vein endothelial cells were used to assess the effects of miRNA mimics or inhibitors on regulation of candidate proteins. RESULTS: In the late diabetic kidney disease cohorts, we identified 17 circulating miRNAs, represented by four exemplars (miR-1287-5p, miR-197-5p, miR-339-5p, and miR-328-3p), that were strongly associated with 10-year risk of ESKD. These miRNAs targeted proteins in the axon guidance pathway. Circulating levels of six of these proteins-most notably, EFNA4 and EPHA2-were strongly associated with 10-year risk of ESKD in all cohorts. Furthermore, circulating levels of these proteins correlated with severity of structural lesions in kidney biopsy specimens. In contrast, expression levels of genes encoding these proteins had no apparent effects on the lesions. In in vitro experiments, mimics of miR-1287-5p and miR-197-5p and inhibitors of miR-339-5p and miR-328-3p upregulated concentrations of EPHA2 in either cell lysate, supernatant, or both. CONCLUSIONS: This study reveals novel mechanisms involved in progression to ESKD and points to the importance of systemic factors in the development of diabetic kidney disease. Some circulating miRNAs and axon guidance pathway proteins represent potential targets for new therapies to prevent and treat this condition.
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