PMID- 37210384
OWN - NLM
STAT- MEDLINE
DCOM- 20230522
LR  - 20230525
IS  - 2041-4889 (Electronic)
VI  - 14
IP  - 5
DP  - 2023 May 20
TI  - Klotho prevents transforming growth factor-beta2-induced senescent-like 
      morphological changes in the retinal pigment epithelium.
PG  - 334
LID - 10.1038/s41419-023-05851-8 [doi]
LID - 334
AB  - Degenerative changes of the retinal pigment epithelium (RPE) triggered by 
      transforming growth factor-beta2 (TGF-beta2) and oxidative stress play a critical role 
      in the progression of age-related macular degeneration (AMD). The expression of 
      alpha-klotho, an antiaging protein, declines with age, increasing the risk factors 
      for age-related diseases. Here, we investigated the protective effects of soluble 
      alpha-klotho on TGF-beta2-induced RPE degeneration. The morphological changes induced by 
      TGF-beta2, including epithelial-mesenchymal transition (EMT), were attenuated in the 
      mouse RPE by the intravitreal injection (IVT) of alpha-klotho. In ARPE19 cells, EMT 
      and morphological alterations by TGF-beta2 were attenuated by co-incubation with 
      alpha-klotho. TGF-beta2 decreased miR-200a accompanied by zinc finger e-box binding 
      homeobox1 (ZEB1) upregulation and EMT, all of which were prevented by alpha-klotho 
      co-treatment. Inhibitor of miR-200a mimicked TGF-beta2-induced morphological 
      changes, which were recovered by ZEP1 silencing, but not by alpha-klotho, implying 
      the upstream regulation of alpha-klotho on miR-200a-ZEP1-EMT axis. alpha-Klotho inhibited 
      receptor binding of TGF-beta2, Smad2/3 phosphorylation, extracellular 
      signal-regulated protein kinase 1/2 (ERK1/2)-a mechanistic target of rapamycin 
      (mTOR) activation and oxidative stress via NADPH oxidase 4 (NOX4) upregulation. 
      Furthermore, alpha-klotho recovered the TGF-beta2-induced mitochondrial activation and 
      superoxide generation. Interestingly, TGF-beta2 upregulated alpha-klotho expression in 
      the RPE cells, and genetic suppression of endogenous alpha-klotho aggravated 
      TGF-beta2-induced oxidative stress and EMT. Lastly, alpha-klotho abrogated 
      senescence-associated signaling molecules and phenotypes induced by long-term 
      incubation with TGF-beta2. Hence, our findings indicate that the antiaging alpha-klotho 
      plays a protective role against EMT and degeneration of the RPE, demonstrating 
      the therapeutic potential for age-related retinal diseases, including the dry 
      type of AMD.
CI  - (c) 2023. The Author(s).
FAU - Jang, Ha Young
AU  - Jang HY
AD  - Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research 
      Institute, Seoul National University Hospital, Seoul, Republic of Korea.
FAU - Kim, Soo-Jin
AU  - Kim SJ
AUID- ORCID: 0000-0002-4989-1372
AD  - Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, 
      Republic of Korea.
AD  - Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, 
      Republic of Korea.
FAU - Park, Kyu-Sang
AU  - Park KS
AUID- ORCID: 0000-0003-0322-9807
AD  - Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, 
      Republic of Korea. qsang@yonsei.ac.kr.
AD  - Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, 
      Republic of Korea. qsang@yonsei.ac.kr.
FAU - Kim, Jeong Hun
AU  - Kim JH
AUID- ORCID: 0000-0003-2957-1766
AD  - Fight against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research 
      Institute, Seoul National University Hospital, Seoul, Republic of Korea. 
      steph25@snu.ac.kr.
AD  - Department of Ophthalmology, College of Medicine, Seoul National University, 
      Seoul, Republic of Korea. steph25@snu.ac.kr.
AD  - Institute of Reproductive Medicine and Population, Seoul National University 
      College of Medicine, Seoul, Republic of Korea. steph25@snu.ac.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230520
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (MicroRNAs)
RN  - 0 (Transforming Growth Factor beta2)
RN  - EC 3.2.1.31 (Kl protein, mouse)
RN  - EC 3.2.1.31 (Klotho Proteins)
SB  - IM
MH  - Animals
MH  - Mice
MH  - Epithelial-Mesenchymal Transition
MH  - *MicroRNAs/metabolism
MH  - *Retinal Pigment Epithelium/metabolism
MH  - Signal Transduction
MH  - Transforming Growth Factor beta2/metabolism
MH  - *Klotho Proteins/metabolism
PMC - PMC10199917
COIS- The authors declare no competing interests.
EDAT- 2023/05/21 01:05
MHDA- 2023/05/22 06:42
PMCR- 2023/05/20
CRDT- 2023/05/20 23:04
PHST- 2022/11/21 00:00 [received]
PHST- 2023/05/04 00:00 [accepted]
PHST- 2023/05/01 00:00 [revised]
PHST- 2023/05/22 06:42 [medline]
PHST- 2023/05/21 01:05 [pubmed]
PHST- 2023/05/20 23:04 [entrez]
PHST- 2023/05/20 00:00 [pmc-release]
AID - 10.1038/s41419-023-05851-8 [pii]
AID - 5851 [pii]
AID - 10.1038/s41419-023-05851-8 [doi]
PST - epublish
SO  - Cell Death Dis. 2023 May 20;14(5):334. doi: 10.1038/s41419-023-05851-8.