PMID- 32867359
OWN - NLM
STAT- MEDLINE
DCOM- 20210225
LR  - 20210225
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 21
IP  - 17
DP  - 2020 Aug 27
TI  - TRPV1 Hyperfunction Involved in Uremic Toxin Indoxyl Sulfate-Mediated Renal 
      Tubular Damage.
LID - 10.3390/ijms21176212 [doi]
LID - 6212
AB  - Indoxyl sulfate (IS) is accumulated during severe renal insufficiency and known 
      for its nephrotoxic properties. Transient receptor potential vanilloid 1 (TRPV1) 
      is present in the kidney and acts as a renal sensor. However, the mechanism 
      underlying IS-mediated renal tubular damage in view of TRPV1 is lacking. Here, we 
      demonstrated that TRPV1 was expressed in tubular cells of Lilly Laboratories 
      cell-porcine kidney 1 (LLC-PK(1)) and Madin-Darby canine kidney cells (MDCK). IS 
      treatment in both cells exhibited tubular damage with increased LDH release and 
      reduced cell viability in dose- and time-dependent manners. MDCK, however, was 
      more vulnerable to IS. We, therefore, investigated MDCK cells to explore a more 
      detailed mechanism. Interestingly, IS-induced tubular damage was markedly 
      attenuated in the presence of selective TRPV1 blockers. IS showed no effect on 
      TRPV1 expression but significantly increased arachidonate 12-lipoxygenase 
      (ALOX12) protein, mRNA expression, and 12(S)-hydroxyeicosatetraenoic acid 
      (12(S)-HETE) amounts in a dose-dependent manner, indicating that the 
      ALOX12/12(S)-HETE pathway induced TRPV1 hyperfunction in IS-mediated 
      tubulotoxicity. Blockade of ALOX12 by cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate or 
      baicalein attenuated the effects of IS. Since aryl hydrocarbon receptor (AhR) 
      activation after IS binding is crucial in mediating cell death, here, we found 
      that the AhR blockade not only ameliorated tubular damage but also attenuated 
      ALOX12 expression and 12(S)-HETE production caused by IS. The uremic toxic 
      adsorbent AST-120, however, showed little effect on ALOX12 and 12(S)-HETE, as 
      well as IS-induced cell damage. These results clearly indicated that IS activated 
      AhR and then upregulated ALOX12, and this induced endovanilloid 12(S)-HETE 
      synthesis and contributed to TRPV1 hyperfunction in IS-treated tubular cells. 
      Further study on TRPV1 may attenuate kidney susceptibility to the functional loss 
      of end-stage kidney disease via IS.
FAU - Lu, Chien-Lin
AU  - Lu CL
AUID- ORCID: 0000-0002-9452-5179
AD  - Division of Nephrology, Department of Medicine, Fu Jen Catholic University 
      Hospital, New Taipei City 24205, Taiwan.
AD  - School of Medicine, Fu Jen Catholic University, New Taipei City 24205, Taiwan.
FAU - Liao, Chun-Hou
AU  - Liao CH
AD  - School of Medicine, Fu Jen Catholic University, New Taipei City 24205, Taiwan.
AD  - Divisions of Urology, Department of Surgery, Cardinal Tien Hospital, New Taipei 
      City 23148, Taiwan.
FAU - Lu, Kuo-Cheng
AU  - Lu KC
AD  - Division of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist 
      Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan.
FAU - Ma, Ming-Chieh
AU  - Ma MC
AD  - School of Medicine, Fu Jen Catholic University, New Taipei City 24205, Taiwan.
LA  - eng
PT  - Journal Article
DEP - 20200827
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Caffeic Acids)
RN  - 0 (Flavanones)
RN  - 0 (Hydroxyeicosatetraenoic Acids)
RN  - 0 (Receptors, Aryl Hydrocarbon)
RN  - 0 (TRPV Cation Channels)
RN  - 0 (cinnamyl-3,4-dihydroxycyanocinnamate)
RN  - 49QAH60606 (baicalein)
RN  - EC 1.13.11.31 (Arachidonate 12-Lipoxygenase)
RN  - N187WK1Y1J (Indican)
SB  - IM
MH  - Animals
MH  - Arachidonate 12-Lipoxygenase/genetics/*metabolism
MH  - Caffeic Acids/pharmacology
MH  - Cell Line
MH  - Cell Survival/drug effects
MH  - Dogs
MH  - Dose-Response Relationship, Drug
MH  - Down-Regulation
MH  - Flavanones/pharmacology
MH  - Hydroxyeicosatetraenoic Acids/*metabolism
MH  - Indican/*adverse effects
MH  - Kidney Tubules/cytology/drug effects/*injuries/metabolism
MH  - Madin Darby Canine Kidney Cells
MH  - Models, Biological
MH  - Receptors, Aryl Hydrocarbon/metabolism
MH  - Swine
MH  - TRPV Cation Channels/*metabolism
MH  - Time
PMC - PMC7503230
OTO - NOTNLM
OT  - 12(S)-hydroxyeicosatetraenoic acid
OT  - arachidonate 12-lipoxygenase
OT  - aryl hydrocarbon receptor
OT  - indoxyl sulfate
OT  - renal tubular damage
OT  - transient receptor potential vanilloid 1
COIS- The authors declare no conflict of interest.
EDAT- 2020/09/02 06:00
MHDA- 2021/02/26 06:00
PMCR- 2020/09/01
CRDT- 2020/09/02 06:00
PHST- 2020/07/29 00:00 [received]
PHST- 2020/08/25 00:00 [revised]
PHST- 2020/08/26 00:00 [accepted]
PHST- 2020/09/02 06:00 [entrez]
PHST- 2020/09/02 06:00 [pubmed]
PHST- 2021/02/26 06:00 [medline]
PHST- 2020/09/01 00:00 [pmc-release]
AID - ijms21176212 [pii]
AID - ijms-21-06212 [pii]
AID - 10.3390/ijms21176212 [doi]
PST - epublish
SO  - Int J Mol Sci. 2020 Aug 27;21(17):6212. doi: 10.3390/ijms21176212.