Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: DrugBank:EXPT01586 (
G418
)
2,237
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The elevated intracellular Ca
2+
and oxidative stress are well-reported mechanisms behind renal tubular epithelial injury initiated by various insults. Given that
TRPV4
and connexin43 (Cx43) channels are activated by a wide range of stimuli and regulate both intracellular Ca
2+
and redox status, we speculated an involvement of these channels in renal tubular cell injury. Here, we tested this possibility and explored the potential underlying mechanisms. Our results demonstrated that exposure of renal tubular epithelial cells to aminoglycoside
G418
led to cell death, which was attenuated by both
TRPV4
and gap junction (Gj) inhibitor. Activation of
TRPV4
caused cell damage, which was associated with an early increase in Cx43 expression and function. Inhibition of Cx43 with chemical inhibitor or siRNA largely prevented
TRPV4
activation-induced cell damage. Further analysis revealed that
TRPV4
agonists elicited a rise in intracellular Ca
2+
and caused a Ca
2+
-dependent elevation in TXNIP (a negative regulator of the antioxidant thioredoxin). In the presence of Gj inhibitor, however, these effects of
TRPV4
were largely prevented. The depletion of intracellular Ca
2+
with Ca
2+
chelator BAPTA-AM or downregulation of TXNIP with siRNA significantly alleviated
TRPV4
activation-initiated cell injury. Collectively, our results point to a critical involvement of
TRPV4
/Cx43 channel interaction in renal tubular cell injury through mechanisms involving a synergetic induction of intracellular Ca
2+
and oxidative stress. Channel interactions could be an important mechanism underlying cell injury. Targeting channels could have therapeutic potential for the treatment of acute tubular cell injury.
...
PMID:Gap junctions amplify TRPV4 activation-initiated cell injury via modification of intracellular Ca
2+
and Ca
2+
-dependent regulation of TXNIP. 3275 16
