Reversal of the renal hyperglycemic memory in diabetic kidney disease by targeting sustained tubular p21 expression

Moh’d Mohanad Al-Dabet, Khurrum Shahzad, Ahmed Elwakiel, Alba Sulaj, Stefan Kopf, Fabian Bock, Ihsan Gadi, Silke Zimmermann, Rajiv Rana, Shruthi Krishnan, Dheerendra Gupta, Jayakumar Manoharan, Sameen Fatima, Sumra Nazir, Constantin Schwab, Ronny Baber, Markus Scholz, Robert Geffers, Peter Rene Mertens, Peter P. Nawroth, John H. Griffin, Maria Keller, Chris Dockendorff, Shrey Kohli () and Berend Isermann ()
Additional contact information
Moh’d Mohanad Al-Dabet: Universitätsklinikum Leipzig, Leipzig University
Khurrum Shahzad: Universitätsklinikum Leipzig, Leipzig University
Ahmed Elwakiel: Universitätsklinikum Leipzig, Leipzig University
Alba Sulaj: University of Heidelberg
Stefan Kopf: University of Heidelberg
Fabian Bock: Universitätsklinikum Leipzig, Leipzig University
Ihsan Gadi: Universitätsklinikum Leipzig, Leipzig University
Silke Zimmermann: Universitätsklinikum Leipzig, Leipzig University
Rajiv Rana: Universitätsklinikum Leipzig, Leipzig University
Shruthi Krishnan: Universitätsklinikum Leipzig, Leipzig University
Dheerendra Gupta: Universitätsklinikum Leipzig, Leipzig University
Jayakumar Manoharan: Universitätsklinikum Leipzig, Leipzig University
Sameen Fatima: Universitätsklinikum Leipzig, Leipzig University
Sumra Nazir: Universitätsklinikum Leipzig, Leipzig University
Constantin Schwab: University of Heidelberg
Ronny Baber: Universitätsklinikum Leipzig, Leipzig University
Markus Scholz: Leipzig University
Robert Geffers: Helmholtz Centre for Infection Research
Peter Rene Mertens: Otto-von-Guericke University
Peter P. Nawroth: University of Heidelberg
John H. Griffin: The Scripps Research Institute
Maria Keller: Obesity and Vascular Research (HI-MAG) of the Helmholtz Center Munich at the University of Leipzig and University Hospital Leipzig
Chris Dockendorff: Marquette University
Shrey Kohli: Universitätsklinikum Leipzig, Leipzig University
Berend Isermann: Universitätsklinikum Leipzig, Leipzig University

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32477-9

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