PMID- 36831311
OWN - NLM
STAT- MEDLINE
DCOM- 20230228
LR  - 20230328
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 12
IP  - 4
DP  - 2023 Feb 17
TI  - Implications of Senescent Cell Burden and NRF2 Pathway in Uremic Calcification: A 
      Translational Study.
LID - 10.3390/cells12040643 [doi]
LID - 643
AB  - Increased senescent cell burden and dysregulation of the nuclear factor erythroid 
      2-related factor 2 (NRF2) pathway have been associated with numerous age-related 
      pathologies; however, their role in promoting vascular calcification (VC) in 
      chronic kidney disease (CKD) has yet to be determined. We investigated whether 
      senescence and NRF2 pathways may serve as drivers of uremia-induced VC using 
      three complementary approaches: a novel model of induced VC in 5/6-nephrectomized 
      rats supplemented with high phosphate and vitamin D; epigastric arteries from CKD 
      patients with established medial calcification; and vascular smooth muscle cells 
      (VSMCs) incubated with uremic serum. Expression of p16(Ink4a) and p21(Cip1), as 
      well as gamma-H2A-positive cells, confirmed increased senescent cell burden at the 
      site of calcium deposits in aortic sections in rats, and was similarly observed 
      in calcified epigastric arteries from CKD patients through increased p16(Ink4a) 
      expression. However, uremic serum-induced VSMC calcification was not accompanied 
      by senescence. Expression of NRF2 and downstream genes, Nqo1 and Sod1, was 
      associated with calcification in uremic rats, while no difference was observed 
      between calcified and non-calcified EAs. Conversely, in vitro uremic serum-driven 
      VC was associated with depleted NRF2 expression. Together, our data strengthen 
      the importance of senescence and NRF2 pathways as potential therapeutic options 
      to combat VC in CKD.
FAU - Laget, Jonas
AU  - Laget J
AUID- ORCID: 0000-0002-9095-7409
AD  - RD-Nephrologie, 34090 Montpellier, France.
AD  - Biocommunication in Cardio-Metabolism (BC2M), University of Montpellier, 34090 
      Montpellier, France.
FAU - Hobson, Sam
AU  - Hobson S
AUID- ORCID: 0000-0002-5880-885X
AD  - Division of Renal Medicine, Department of Clinical Science, Intervention and 
      Technology, Karolinska Institutet, 141 52 Stockholm, Sweden.
FAU - Muyor, Karen
AU  - Muyor K
AD  - RD-Nephrologie, 34090 Montpellier, France.
FAU - Duranton, Flore
AU  - Duranton F
AUID- ORCID: 0000-0003-3202-0551
AD  - RD-Nephrologie, 34090 Montpellier, France.
FAU - Cortijo, Irene
AU  - Cortijo I
AD  - RD-Nephrologie, 34090 Montpellier, France.
AD  - Biocommunication in Cardio-Metabolism (BC2M), University of Montpellier, 34090 
      Montpellier, France.
FAU - Bartochowski, Piotr
AU  - Bartochowski P
AD  - RD-Nephrologie, 34090 Montpellier, France.
AD  - Biocommunication in Cardio-Metabolism (BC2M), University of Montpellier, 34090 
      Montpellier, France.
FAU - Jover, Bernard
AU  - Jover B
AUID- ORCID: 0000-0001-5826-5755
AD  - RD-Nephrologie, 34090 Montpellier, France.
FAU - Lajoix, Anne-Dominique
AU  - Lajoix AD
AUID- ORCID: 0000-0002-5912-5233
AD  - Biocommunication in Cardio-Metabolism (BC2M), University of Montpellier, 34090 
      Montpellier, France.
FAU - Soderberg, Magnus
AU  - Soderberg M
AUID- ORCID: 0000-0003-0946-5202
AD  - Pathology, Clinical Pharmacology and Safety Sciences, R&D AstraZeneca, 431 50 
      Gothenburg, Sweden.
FAU - Ebert, Thomas
AU  - Ebert T
AUID- ORCID: 0000-0003-1683-9276
AD  - Division of Renal Medicine, Department of Clinical Science, Intervention and 
      Technology, Karolinska Institutet, 141 52 Stockholm, Sweden.
AD  - Medical Department III-Endocrinology, Nephrology, Rheumatology, University of 
      Leipzig Medical Center, 04109 Leipzig, Germany.
FAU - Stenvinkel, Peter
AU  - Stenvinkel P
AUID- ORCID: 0000-0002-8785-4820
AD  - Division of Renal Medicine, Department of Clinical Science, Intervention and 
      Technology, Karolinska Institutet, 141 52 Stockholm, Sweden.
FAU - Argiles, Angel
AU  - Argiles A
AUID- ORCID: 0000-0001-7029-4532
AD  - RD-Nephrologie, 34090 Montpellier, France.
FAU - Kublickiene, Karolina
AU  - Kublickiene K
AUID- ORCID: 0000-0002-4841-6836
AD  - Division of Renal Medicine, Department of Clinical Science, Intervention and 
      Technology, Karolinska Institutet, 141 52 Stockholm, Sweden.
FAU - Gayrard, Nathalie
AU  - Gayrard N
AUID- ORCID: 0000-0001-8283-8429
AD  - RD-Nephrologie, 34090 Montpellier, France.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230217
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p16)
SB  - IM
MH  - Rats
MH  - Animals
MH  - NF-E2-Related Factor 2/metabolism
MH  - Cyclin-Dependent Kinase Inhibitor p16/metabolism
MH  - Muscle, Smooth, Vascular/metabolism
MH  - *Vascular Calcification/genetics
MH  - *Renal Insufficiency, Chronic/pathology
MH  - Cellular Senescence
PMC - PMC9954542
OTO - NOTNLM
OT  - NRF2
OT  - kidney failure
OT  - senescence
OT  - subtotal nephrectomy
OT  - vascular calcification
COIS- The authors declare no conflict of interest.
EDAT- 2023/02/26 06:00
MHDA- 2023/03/03 06:00
PMCR- 2023/02/17
CRDT- 2023/02/25 01:35
PHST- 2023/01/10 00:00 [received]
PHST- 2023/02/06 00:00 [revised]
PHST- 2023/02/13 00:00 [accepted]
PHST- 2023/02/25 01:35 [entrez]
PHST- 2023/02/26 06:00 [pubmed]
PHST- 2023/03/03 06:00 [medline]
PHST- 2023/02/17 00:00 [pmc-release]
AID - cells12040643 [pii]
AID - cells-12-00643 [pii]
AID - 10.3390/cells12040643 [doi]
PST - epublish
SO  - Cells. 2023 Feb 17;12(4):643. doi: 10.3390/cells12040643.