PMID- 33044867
OWN - NLM
STAT- MEDLINE
DCOM- 20201208
LR  - 20211204
IS  - 1522-1466 (Electronic)
IS  - 1931-857X (Print)
IS  - 1522-1466 (Linking)
VI  - 319
IP  - 5
DP  - 2020 Nov 1
TI  - Involvement of the CDKL5-SOX9 signaling axis in rhabdomyolysis-associated acute 
      kidney injury.
PG  - F920-F929
LID - 10.1152/ajprenal.00429.2020 [doi]
AB  - Acute kidney injury (AKI) is a common clinical syndrome associated with adverse 
      short- and long-term sequelae. Renal tubular epithelial cell (RTEC) dysfunction 
      and cell death are among the key pathological features of AKI. Diverse systemic 
      and localized stress conditions such as sepsis, rhabdomyolysis, cardiac surgery, 
      and nephrotoxic drugs can trigger RTEC dysfunction. Through an unbiased RNA 
      inhibition screen, we recently identified cyclin-dependent kinase-like 5 (Cdkl5), 
      also known as serine/threonine kinase-9, as a critical regulator of RTEC 
      dysfunction associated with nephrotoxic and ischemia-associated AKI. In the 
      present study, we examined the role of Cdkl5 in rhabdomyolysis-associated AKI. 
      Using activation-specific antibodies and kinase assays, we found that Cdkl5 is 
      activated in RTECs early during the development of rhabdomyolysis-associated AKI. 
      Furthermore, we found that RTEC-specific Cdkl5 gene ablation mitigates 
      rhabdomyolysis-associated renal impairment. In addition, the small-molecule 
      kinase inhibitor AST-487 alleviated rhabdomyolysis-associated AKI in a 
      Cdkl5-dependent manner. Mechanistically, we demonstrated that Cdkl5 
      phosphorylates the transcriptional regulator sex-determining region Y box 9 
      (Sox9) and suppresses its protective function under stress conditions. On the 
      basis of these results, we propose that, by suppressing the protective 
      Sox9-directed transcriptional program, Cdkl5 contributes to 
      rhabdomyolysis-associated renal impairment. All together, the present study 
      identified Cdkl5 as a critical stress-induced kinase that drives RTEC dysfunction 
      and kidney injury linked with distinct etiologies.
FAU - Kim, Ji Young
AU  - Kim JY
AD  - Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive 
      Cancer Center, The Ohio State University, Columbus, Ohio.
FAU - Bai, Yuntao
AU  - Bai Y
AD  - Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive 
      Cancer Center, The Ohio State University, Columbus, Ohio.
FAU - Jayne, Laura A
AU  - Jayne LA
AD  - Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive 
      Cancer Center, The Ohio State University, Columbus, Ohio.
FAU - Cianciolo, Rachel E
AU  - Cianciolo RE
AD  - Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio 
      State University, Columbus, Ohio.
FAU - Bajwa, Amandeep
AU  - Bajwa A
AD  - Transplant Research Institute, James D. Eason Transplant Institute, Department of 
      Surgery, College of Medicine, The University of Tennessee Health Science Center, 
      Memphis, Tennessee.
FAU - Pabla, Navjot Singh
AU  - Pabla NS
AD  - Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive 
      Cancer Center, The Ohio State University, Columbus, Ohio.
LA  - eng
GR  - R01 DK117183/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20201012
PL  - United States
TA  - Am J Physiol Renal Physiol
JT  - American journal of physiology. Renal physiology
JID - 100901990
RN  - 0 (SOX9 Transcription Factor)
RN  - 0 (SOX9 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.22 (CDKL5 protein, human)
SB  - IM
CIN - Am J Physiol Renal Physiol. 2020 Nov 1;319(5):F865-F867. PMID: 33073588
MH  - Acute Kidney Injury/*metabolism/pathology
MH  - Cell Death/physiology
MH  - Epithelial Cells/*metabolism
MH  - Humans
MH  - Kidney/metabolism
MH  - Kidney Tubules/*metabolism
MH  - Phosphorylation
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Rhabdomyolysis/chemically induced
MH  - SOX9 Transcription Factor/*metabolism
MH  - Signal Transduction/physiology
PMC - PMC7789981
OTO - NOTNLM
OT  - acute kidney injury
OT  - cyclin-dependent kinase-like 5
OT  - renal tubular epithelial cells
OT  - rhabdomyolysis
OT  - sex-determining region Y box 9
COIS- No conflicts of interest, financial or otherwise, are declared by the authors.
EDAT- 2020/10/13 06:00
MHDA- 2020/12/15 06:00
PMCR- 2021/11/01
CRDT- 2020/10/12 17:08
PHST- 2020/10/13 06:00 [pubmed]
PHST- 2020/12/15 06:00 [medline]
PHST- 2020/10/12 17:08 [entrez]
PHST- 2021/11/01 00:00 [pmc-release]
AID - F-00429-2020 [pii]
AID - 10.1152/ajprenal.00429.2020 [doi]
PST - ppublish
SO  - Am J Physiol Renal Physiol. 2020 Nov 1;319(5):F920-F929. doi: 
      10.1152/ajprenal.00429.2020. Epub 2020 Oct 12.