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Sphingosine 1-phosphate receptor-1 enhances mitochondrial function and reduces
cisplatin-induced tubule injury
#MMPMID25145931
Bajwa A
; Rosin DL
; Chroscicki P
; Lee S
; Dondeti K
; Ye H
; Kinsey GR
; Stevens BK
; Jobin K
; Kenwood BM
; Hoehn KL
; Lynch KR
; Okusa MD
J Am Soc Nephrol
2015[Apr]; 26
(4
): 908-25
PMID25145931
show ga
Sphingosine 1-phosphate (S1P), the natural sphingolipid ligand for a family of
five G protein- coupled receptors (S1P1-S1P5Rs), regulates cell survival and
lymphocyte circulation. We have shown that the pan-S1PR agonist, FTY720,
attenuates kidney ischemia-reperfusion injury by directly activating S1P1 on
proximal tubule (PT) cells, independent of the canonical lymphopenic effects of
S1P1 activation on B and T cells. FTY720 also reduces cisplatin-induced AKI.
Therefore, in this study, we used conditional PT-S1P1-null (PepckCreS1pr1(fl/fl))
and control (PepckCreS1pr1(w/wt)) mice to determine whether the protective effect
of FTY720 in AKI is mediated by PT-S1P1. Cisplatin induced more renal injury in
PT-S1P1-null mice than in controls. Although FTY720 produced lymphopenia in both
control and PT-S1P1-null mice, it reduced injury only in control mice.
Furthermore, the increase in proinflammatory cytokine (CXCL1, MCP-1, TNF-?, and
IL-6) expression and infiltration of neutrophils and macrophages induced by
cisplatin treatment was attenuated by FTY720 in control mice but not in
PT-S1P1-null mice. Similarly, S1P1 deletion rendered cultured PT cells more
susceptible to cisplatin-induced injury, whereas S1P1 overexpression protected PT
cells from injury and preserved mitochondrial function. We conclude that S1P1 may
have an important role in stabilizing mitochondrial function and that FTY720
administration represents a novel strategy in the prevention of cisplatin-induced
AKI.
|Acute Kidney Injury/chemically induced/*prevention & control
[MESH]
|Animals
[MESH]
|Apoptosis/drug effects
[MESH]
|Cell Respiration
[MESH]
|Cisplatin
[MESH]
|Drug Evaluation, Preclinical
[MESH]
|Epithelial Cells/drug effects
[MESH]
|Fingolimod Hydrochloride
[MESH]
|Kidney Tubules, Proximal/*drug effects
[MESH]
|Male
[MESH]
|Mice, Inbred C57BL
[MESH]
|Mitochondria/*drug effects
[MESH]
|Mitochondrial Dynamics
[MESH]
|Propylene Glycols/pharmacology/*therapeutic use
[MESH]
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