Clopidogrel attenuates lithium-induced alterations in renal water and sodium channels/transporters in mice View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-09-19

AUTHORS

Yue Zhang, János Peti-Peterdi, Kristina M. Heiney, Anne Riquier-Brison, Noel G. Carlson, Christa E. Müller, Carolyn M. Ecelbarger, Bellamkonda K. Kishore

ABSTRACT

Lithium (Li) administration causes deranged expression and function of renal aquaporins and sodium channels/transporters resulting in nephrogenic diabetes insipidus (NDI). Extracellular nucleotides (ATP/ADP/UTP), via P2 receptors, regulate these transport functions. We tested whether clopidogrel bisulfate (CLPD), an antagonist of ADP-activated P2Y12 receptor, would affect Li-induced alterations in renal aquaporins and sodium channels/transporters. Adult mice were treated for 14 days with CLPD and/or Li and euthanized. Urine and kidneys were collected for analysis. When administered with Li, CLPD ameliorated polyuria, attenuated the rise in urine prostaglandin E2 (PGE2), and resulted in significantly higher urinary arginine vasopressin (AVP) and aldosterone levels as compared to Li treatment alone. However, urine sodium excretion remained elevated. Semi-quantitative immunoblotting revealed that CLPD alone increased renal aquaporin 2 (AQP2), Na-K-2Cl cotransporter (NKCC2), Na-Cl cotransporter (NCC), and the subunits of the epithelial Na channel (ENaC) in medulla by 25–130 %. When combined with Li, CLPD prevented downregulation of AQP2, Na-K-ATPase, and NKCC2 but was less effective against downregulation of cortical α- or γ-ENaC (70 kDa band). Thus, CLPD primarily attenuated Li-induced downregulation of proteins involved in water conservation (AVP-sensitive), with modest effects on aldosterone-sensitive proteins potentially explaining sustained natriuresis. Confocal immunofluorescence microscopy revealed strong labeling for P2Y12-R in proximal tubule brush border and blood vessels in the cortex and less intense labeling in medullary thick ascending limb and the collecting ducts. Therefore, there is the potential for CLPD to be directly acting at the tubule sites to mediate these effects. In conclusion, P2Y12-R may represent a novel therapeutic target for Li-induced NDI. More... »

PAGES

507-518

References to SciGraph publications

Journal

TITLE

Purinergic Signalling

ISSUE

4

VOLUME

11

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s11302-015-9469-0

DOI

http://dx.doi.org/10.1007/s11302-015-9469-0

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1001216094

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/26386699


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29 schema:description Lithium (Li) administration causes deranged expression and function of renal aquaporins and sodium channels/transporters resulting in nephrogenic diabetes insipidus (NDI). Extracellular nucleotides (ATP/ADP/UTP), via P2 receptors, regulate these transport functions. We tested whether clopidogrel bisulfate (CLPD), an antagonist of ADP-activated P2Y12 receptor, would affect Li-induced alterations in renal aquaporins and sodium channels/transporters. Adult mice were treated for 14 days with CLPD and/or Li and euthanized. Urine and kidneys were collected for analysis. When administered with Li, CLPD ameliorated polyuria, attenuated the rise in urine prostaglandin E2 (PGE2), and resulted in significantly higher urinary arginine vasopressin (AVP) and aldosterone levels as compared to Li treatment alone. However, urine sodium excretion remained elevated. Semi-quantitative immunoblotting revealed that CLPD alone increased renal aquaporin 2 (AQP2), Na-K-2Cl cotransporter (NKCC2), Na-Cl cotransporter (NCC), and the subunits of the epithelial Na channel (ENaC) in medulla by 25–130 %. When combined with Li, CLPD prevented downregulation of AQP2, Na-K-ATPase, and NKCC2 but was less effective against downregulation of cortical α- or γ-ENaC (70 kDa band). Thus, CLPD primarily attenuated Li-induced downregulation of proteins involved in water conservation (AVP-sensitive), with modest effects on aldosterone-sensitive proteins potentially explaining sustained natriuresis. Confocal immunofluorescence microscopy revealed strong labeling for P2Y12-R in proximal tubule brush border and blood vessels in the cortex and less intense labeling in medullary thick ascending limb and the collecting ducts. Therefore, there is the potential for CLPD to be directly acting at the tubule sites to mediate these effects. In conclusion, P2Y12-R may represent a novel therapeutic target for Li-induced NDI.
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37 ATPase
38 E2
39 ENaC
40 Li
41 Li treatment
42 NKCC2
43 Na
44 Na channels
45 Na-Cl cotransporter
46 Na-K-2Cl cotransporter
47 P2 receptors
48 P2Y12 receptor
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51 adult mice
52 aldosterone levels
53 aldosterone-sensitive proteins
54 alterations
55 analysis
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58 aquaporin 2
59 aquaporins
60 arginine
61 ascending limb
62 bisulfate
63 blood vessels
64 border
65 brush border
66 channels
67 channels/transporters
68 clopidogrel
69 clopidogrel bisulfate
70 conclusion
71 confocal immunofluorescence microscopy
72 conservation
73 cortex
74 cotransporter
75 days
76 diabetes insipidus
77 downregulation
78 downregulation of AQP2
79 downregulation of proteins
80 duct
81 effect
82 epithelial Na channel
83 excretion
84 expression
85 extracellular nucleotides
86 function
87 higher urinary arginine
88 immunoblotting
89 immunofluorescence microscopy
90 insipidus
91 intense labeling
92 kidney
93 labeling
94 levels
95 limb
96 lithium administration
97 lithium-induced alterations
98 medulla
99 medullary thick ascending limb
100 mice
101 microscopy
102 modest effect
103 natriuresis
104 nephrogenic diabetes insipidus
105 novel therapeutic target
106 nucleotides
107 polyuria
108 potential
109 prostaglandin E2
110 protein
111 proximal tubule brush border
112 receptors
113 renal aquaporin 2
114 renal aquaporins
115 renal water
116 rise
117 semi-quantitative immunoblotting
118 sites
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120 sodium excretion
121 strong labeling
122 subunits
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124 target
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126 thick ascending limb
127 transport function
128 transporters
129 treatment
130 tubule brush border
131 tubule sites
132 urinary arginine
133 urine
134 urine prostaglandin E2
135 urine sodium excretion
136 vessels
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