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Reversal of the renal hyperglycemic memory in diabetic kidney disease by targeting sustained tubular p21 expression.
Al-Dabet, Moh'd Mohanad; Shahzad, Khurrum; Elwakiel, Ahmed; Sulaj, Alba; Kopf, Stefan; Bock, Fabian; Gadi, Ihsan; Zimmermann, Silke; Rana, Rajiv; Krishnan, Shruthi; Gupta, Dheerendra; Manoharan, Jayakumar; Fatima, Sameen; Nazir, Sumra; Schwab, Constantin; Baber, Ronny; Scholz, Markus; Geffers, Robert; Mertens, Peter Rene; Nawroth, Peter P; Griffin, John H; Keller, Maria; Dockendorff, Chris; Kohli, Shrey; Isermann, Berend.
Afiliação
  • Al-Dabet MM; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Universitätsklinikum Leipzig, Leipzig University, Leipzig, Germany.
  • Shahzad K; Department of Medical Laboratories, Faculty of Health Sciences, American University of Madaba (AUM), Amman, Jordan.
  • Elwakiel A; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Universitätsklinikum Leipzig, Leipzig University, Leipzig, Germany.
  • Sulaj A; Department of Biotechnology, University of Sargodha, Sargodha, Pakistan.
  • Kopf S; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Universitätsklinikum Leipzig, Leipzig University, Leipzig, Germany.
  • Bock F; Internal Medicine I and Clinical Chemistry, German Diabetes Center (DZD), University of Heidelberg, Heidelberg, Germany.
  • Gadi I; Internal Medicine I and Clinical Chemistry, German Diabetes Center (DZD), University of Heidelberg, Heidelberg, Germany.
  • Zimmermann S; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Universitätsklinikum Leipzig, Leipzig University, Leipzig, Germany.
  • Rana R; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Krishnan S; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Universitätsklinikum Leipzig, Leipzig University, Leipzig, Germany.
  • Gupta D; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Universitätsklinikum Leipzig, Leipzig University, Leipzig, Germany.
  • Manoharan J; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Universitätsklinikum Leipzig, Leipzig University, Leipzig, Germany.
  • Fatima S; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Universitätsklinikum Leipzig, Leipzig University, Leipzig, Germany.
  • Nazir S; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Universitätsklinikum Leipzig, Leipzig University, Leipzig, Germany.
  • Schwab C; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Universitätsklinikum Leipzig, Leipzig University, Leipzig, Germany.
  • Baber R; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Universitätsklinikum Leipzig, Leipzig University, Leipzig, Germany.
  • Scholz M; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Universitätsklinikum Leipzig, Leipzig University, Leipzig, Germany.
  • Geffers R; Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
  • Mertens PR; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Universitätsklinikum Leipzig, Leipzig University, Leipzig, Germany.
  • Nawroth PP; Leipzig Medical Biobank, Leipzig University, Leipzig, Germany.
  • Griffin JH; Institute for Medical Informatics, Statistics and Epidemiology, Leipzig University, Leipzig, Germany.
  • Keller M; Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany.
  • Dockendorff C; Clinic of Nephrology and Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, Magdeburg, Germany.
  • Kohli S; Internal Medicine I and Clinical Chemistry, German Diabetes Center (DZD), University of Heidelberg, Heidelberg, Germany.
  • Isermann B; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.
Nat Commun ; 13(1): 5062, 2022 08 27.
Article em En | MEDLINE | ID: mdl-36030260
A major obstacle in diabetes is the metabolic or hyperglycemic memory, which lacks specific therapies. Here we show that glucose-mediated changes in gene expression largely persist in diabetic kidney disease (DKD) despite reversing hyperglycemia. The senescence-associated cyclin-dependent kinase inhibitor p21 (Cdkn1a) was the top hit among genes persistently induced by hyperglycemia and was associated with induction of the p53-p21 pathway. Persistent p21 induction was confirmed in various animal models, human samples and in vitro models. Tubular and urinary p21-levels were associated with DKD severity and remained elevated despite improved blood glucose levels in humans. Mechanistically, sustained tubular p21 expression in DKD is linked to demethylation of its promoter and reduced DNMT1 expression. Two disease resolving agents, protease activated protein C (3K3A-aPC) and parmodulin-2, reversed sustained tubular p21 expression, tubular senescence, and DKD. Thus, p21-dependent tubular senescence is a pathway contributing to the hyperglycemic memory, which can be therapeutically targeted.
Assuntos

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Diabetes Mellitus / Nefropatias Diabéticas / Inibidor de Quinase Dependente de Ciclina p21 / Hiperglicemia Limite: Animals / Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Alemanha

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Diabetes Mellitus / Nefropatias Diabéticas / Inibidor de Quinase Dependente de Ciclina p21 / Hiperglicemia Limite: Animals / Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Alemanha