|
| Status |
Public on Jun 28, 2022 |
| Title |
Reversal of the renal hyperglycemic memory by targeting sustained tubular p21 expression |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
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, glucose-induced and sustained tubular p21 expression is linked to demethylation of its promoter and reduced DNMT1 expression. Exploiting signaling of the disease resolving protease activated protein C (3K3A-aPC, 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.
|
| |
|
| Overall design |
In wild-type mice (C57BL/6, age 8-10 weeks) mice hyperglycemia was induced using low dose streptozotocin (STZ) injection (intraperitoneally, 60 mg/kg body weight, for 5 consecutive days). Subsets of mice were treated with a sodium-glucose co-transporter 2 inhibitor (SGLT-2i, Dapagliflozin®, 25 mg/kg body weight, in the drinking water . Mice were sacrificed at the end of study period and kidney samples were isolated and RNAseq was performed.
|
| |
|
| Contributor(s) |
Isermann B, Geffers R |
| Citation(s) |
36030260 |
| |
| Submission date |
Apr 01, 2022 |
| Last update date |
Sep 15, 2022 |
| Contact name |
Robert Geffers |
| E-mail(s) |
robert.geffers@helmholtz-hzi.de
|
| Phone |
+49 531-6181-3058
|
| Organization name |
HCI - Helmholtz Centre for Infection Research
|
| Department |
Dep. Molecular Bacteriology
|
| Lab |
Genome Analytics
|
| Street address |
Inhoffenstr. 7
|
| City |
Braunschweig |
| ZIP/Postal code |
38124 |
| Country |
Germany |
| |
|
| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
|
| Samples (7)
|
|
| Relations |
| BioProject |
PRJNA822123 |
Less...
More...