PMID- 35290515
OWN - NLM
STAT- MEDLINE
DCOM- 20220426
LR  - 20230915
IS  - 1432-0878 (Electronic)
IS  - 0302-766X (Print)
IS  - 0302-766X (Linking)
VI  - 388
IP  - 2
DP  - 2022 May
TI  - The ability of remaining glomerular podocytes to adapt to the loss of their 
      neighbours decreases with age.
PG  - 439-451
LID - 10.1007/s00441-022-03611-2 [doi]
AB  - Progressive podocyte loss is a feature of healthy ageing. While previous studies 
      have reported age-related changes in podocyte number, density and size and 
      associations with proteinuria and glomerulosclerosis, few studies have examined 
      how the response of remaining podocytes to podocyte depletion changes with age. 
      Mild podocyte depletion was induced in Pod(Cre)iDTR mice aged 1, 6, 12 and 
      18 months via intraperitoneal administration of diphtheria toxin. Control mice 
      received intraperitoneal vehicle. Podometrics, proteinuria and glomerular 
      pathology were assessed, together with podocyte expression of p-rp-S6, a 
      phosphorylation target that represents activity of the mammalian target of 
      rapamycin (mTOR). Podocyte number per glomerulus did not change in control mice 
      in the 18-month time period examined. However, control mice at 18 months had the 
      largest podocytes and the lowest podocyte density. Podocyte depletion at 1, 6 and 
      12 months resulted in mild albuminuria but no glomerulosclerosis, whereas similar 
      levels of podocyte depletion at 18 months resulted in both albuminuria and 
      glomerulosclerosis. Following podocyte depletion at 6 and 12 months, the number 
      of p-rp-S6 positive podocytes increased significantly, and this was associated 
      with an adaptive increase in podocyte volume. However, at 18 months of age, 
      remaining podocytes were unable to further elevate mTOR expression or undergo 
      hypertrophic adaptation in response to mild podocyte depletion, resulting in 
      marked glomerular pathology. These findings demonstrate the importance of 
      mTORC1-mediated podocyte hypertrophy in both physiological (ageing) and adaptive 
      settings, highlighting a functional limit to podocyte hypertrophy reached under 
      physiological conditions.
CI  - (c) 2022. The Author(s).
FAU - van der Wolde, James
AU  - van der Wolde J
AD  - Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery 
      Institute, Monash University, Melbourne, Australia.
FAU - Haruhara, Kotaro
AU  - Haruhara K
AD  - Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery 
      Institute, Monash University, Melbourne, Australia.
AD  - Division of Nephrology and Hypertension, Jikei University School of Medicine, 
      Tokyo, Japan.
FAU - Puelles, Victor G
AU  - Puelles VG
AD  - Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery 
      Institute, Monash University, Melbourne, Australia.
AD  - Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, 
      Germany.
FAU - Nikolic-Paterson, David
AU  - Nikolic-Paterson D
AD  - Departments of Nephrology and Medicine, Monash Health and Monash University, 
      Clayton, Vic, Australia.
FAU - Bertram, John F
AU  - Bertram JF
AD  - Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery 
      Institute, Monash University, Melbourne, Australia. john.bertram@monash.edu.
FAU - Cullen-McEwen, Luise A
AU  - Cullen-McEwen LA
AUID- ORCID: 0000-0003-2229-5762
AD  - Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery 
      Institute, Monash University, Melbourne, Australia. 
      luise.cullen-mcewen@monash.edu.
LA  - eng
PT  - Journal Article
DEP - 20220315
PL  - Germany
TA  - Cell Tissue Res
JT  - Cell and tissue research
JID - 0417625
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - *Aging
MH  - Albuminuria/metabolism/pathology
MH  - Animals
MH  - Female
MH  - Hypertrophy/metabolism/pathology
MH  - Male
MH  - Mice
MH  - *Podocytes/cytology
MH  - Proteinuria
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC9035415
OTO - NOTNLM
OT  - Ageing
OT  - Glomerulus
OT  - Kidney
OT  - Podocyte
OT  - mTOR
COIS- The authors declare no competing interests.
EDAT- 2022/03/16 06:00
MHDA- 2022/04/27 06:00
PMCR- 2022/03/15
CRDT- 2022/03/15 17:19
PHST- 2021/12/01 00:00 [received]
PHST- 2022/03/01 00:00 [accepted]
PHST- 2022/03/16 06:00 [pubmed]
PHST- 2022/04/27 06:00 [medline]
PHST- 2022/03/15 17:19 [entrez]
PHST- 2022/03/15 00:00 [pmc-release]
AID - 10.1007/s00441-022-03611-2 [pii]
AID - 3611 [pii]
AID - 10.1007/s00441-022-03611-2 [doi]
PST - ppublish
SO  - Cell Tissue Res. 2022 May;388(2):439-451. doi: 10.1007/s00441-022-03611-2. Epub 
      2022 Mar 15.