INT244386

Context Info Confidence 0.58 First Reported 2005 Last Reported 2008 Negated 0 Speculated 0 Reported most in Body Documents 10 Total Number 19 Disease Relevance 18.39 Pain Relevance 4.50

plasma membrane (Slc12a2)

Anatomy Link Frequency kidney 6 spinal cord 4 neurons 4 nephron 2 proximal 2 Slc12a2 (Rattus norvegicus)

Pain Link Frequency Relevance Heat Hyperalgesia 104 100.00 qutenza 16 99.60 Spinal cord 112 99.40 Inflammatory mediators 184 98.60 Pain 28 97.76 Eae 4 96.56 Inflammation 76 96.40 imagery 20 94.88 Inflammatory stimuli 8 92.56 Thermal hyperalgesia 80 91.24

Disease Link Frequency Relevance Heat Hyperalgesia 216 100.00 Spinal Cord Injury 288 99.96 Chronic Renal Failure 1240 99.84 INFLAMMATION 268 98.40 Pain 28 97.76 Injury 60 97.24 Neuropathic Pain 124 95.04 Contusions 16 94.80 Pruritus 8 91.72 Bartter Syndrome 10 90.32

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Key:

Protein

Mutation

Event

Anatomy

Negation

Speculation

Pain term

Disease term

This data indicate a significant increase in the expression of NKCC1 and, conversely, a decrease in KCC2 expression at the epicenter on day 14 post-SCI (prior to the chronic phase of post-SCI neuropathic hyperalgesia).

Positive_regulation (increase) of Gene_expression (expression) of NKCC1 associated with hyperalgesia, spinal cord injury and neuropathic pain

1) Confidence 0.58 Published 2008 Journal Mol Pain Section Body Doc Link PMC2561007 Disease Relevance 1.35 Pain Relevance 0.36

For DRG neurons, the expression of NKCC1 is well documented [13,22], while the expression of KCC2 is controversial [23,24].

Positive_regulation (documented) of Gene_expression (expression) of NKCC1 in neurons

2) Confidence 0.47 Published 2008 Journal Mol Pain Section Body Doc Link PMC2526990 Disease Relevance 0.45 Pain Relevance 0.46

The effect of the mediators is consistent with increased Cl- accumulation, as NKCC1 expression is enhanced, while KCC2 expression is attenuated.

Positive_regulation (enhanced) of Gene_expression (expression) of NKCC1

3) Confidence 0.47 Published 2008 Journal Mol Pain Section Body Doc Link PMC2526990 Disease Relevance 0.24 Pain Relevance 0.12

We find that inflammatory mediators cause an increase of Cl- levels in DRG neurons which correlates with enhanced NKCC1 expression and decreased KCC2 expression.

Positive_regulation (enhanced) of Gene_expression (expression) of NKCC1 in neurons associated with inflammatory mediators

4) Confidence 0.44 Published 2008 Journal Mol Pain Section Body Doc Link PMC2526990 Disease Relevance 0.56 Pain Relevance 0.47

After 3 hours of treatment, the efficiency of Cl- accumulation is further enhanced through upregulation of NKCC1 expression and reduced expression of the K+-Cl- co-transporter KCC2.

Positive_regulation (upregulation) of Gene_expression (expression) of NKCC1

5) Confidence 0.44 Published 2008 Journal Mol Pain Section Body Doc Link PMC2526990 Disease Relevance 0.74 Pain Relevance 0.52

Changes of NKCC1 and KCC2 in hyperalgesia rats following SCI

Positive_regulation (following) of Gene_expression (Changes) of NKCC1 associated with hyperalgesia and spinal cord injury

6) Confidence 0.42 Published 2008 Journal Mol Pain Section Body Doc Link PMC2561007 Disease Relevance 1.78 Pain Relevance 0.56

Moreover, an increase in NKCC1 protein expression occurred in the lesion epicenter of the spinal cord during day 2–14 post-SCI and peaked on day 14 post-SCI (p < 0.05).

Positive_regulation (increase) of Gene_expression (expression) of NKCC1 in spinal cord associated with spinal cord injury and spinal cord

7) Confidence 0.39 Published 2008 Journal Mol Pain Section Abstract Doc Link PMC2561007 Disease Relevance 1.80 Pain Relevance 0.88

After intra-colonic capsaicin injection in mice, NKCC1 plasma membrane expression and phosphorylation are increased in the dorsal spinal cord, although it is unknown whether it is accompanied with KCC2 down-regulation [16].

Positive_regulation (increased) of Gene_expression (expression) of NKCC1 in spinal cord associated with qutenza and spinal cord

8) Confidence 0.37 Published 2008 Journal Mol Pain Section Body Doc Link PMC2561007 Disease Relevance 1.13 Pain Relevance 1.10

Furthermore, they are sufficient to trigger the switch as shown with in vitro or in vivo antisense inhibition [124, 261, 302,351], overexpression of KCC2 or NKCC1 [6, 39, 165] or pharmacological inhibitors of CCCs [333].

Positive_regulation (overexpression) of Gene_expression (overexpression) of NKCC1

9) Confidence 0.21 Published 2008 Journal Current Neuropharmacology Section Body Doc Link PMC2645547 Disease Relevance 0 Pain Relevance 0.04

In the present study, we demonstrated an increase of BSC-1 protein expression in CRF rats treated with vehicle compared with sham-operated rats, and this was consistent with our previous study demonstrating an increase of density per nephron of BSC-1 in CRF rats (although the previous study demonstrated unchanged protein expression of BSC-1 between CRF and sham-operated rats (6)).

Positive_regulation (increase) of Gene_expression (expression) of BSC-1 in nephron associated with chronic renal failure

10) Confidence 0.14 Published 2005 Journal Journal of Korean Medical Science Section Body Doc Link PMC2808601 Disease Relevance 0.63 Pain Relevance 0

This could induce an increased loading of NaCl and fluid into the TAL, thereby increasing the BSC-1 expression.

Positive_regulation (increasing) of Gene_expression (expression) of BSC-1

11) Confidence 0.14 Published 2005 Journal Journal of Korean Medical Science Section Body Doc Link PMC2808601 Disease Relevance 0.43 Pain Relevance 0

The decreased AQP2 expression in CRF rats was not altered in response to candesartan treatment; 3) Candesartan treatment was associated with decreased NHE3 and TSC expression in CRF, which could be due to the Ang II AT1 receptor blockade and/or decreased aldosterone levels; and 4) BSC-1 expression was increased in both CRF groups and the increased expression of BSC-1 was more prominent in candesartan-treated CRF rats compared with vehicle-treated CRF rats.

Positive_regulation (increased) of Gene_expression (expression) of BSC-1 associated with chronic renal failure

12) Confidence 0.14 Published 2005 Journal Journal of Korean Medical Science Section Body Doc Link PMC2808601 Disease Relevance 1.26 Pain Relevance 0

Semi-quantitative immunoblotting of whole kidney protein samples from CRF rats and sham-operated rats demonstrated that CRF rats, both vehicle-treated and candesartan-treated, had significantly increased BSC-1 expression, compared with sham-operated controls (Fig. 4, Table 2).

Positive_regulation (increased) of Gene_expression (expression) of BSC-1 in kidney associated with chronic renal failure

13) Confidence 0.14 Published 2005 Journal Journal of Korean Medical Science Section Body Doc Link PMC2808601 Disease Relevance 1.48 Pain Relevance 0

Kidney expression of BSC-1 was increased in CRF rats both vehicle-treated (CRF-V) and candesartan-treated (CRF-C)

Positive_regulation (increased) of Gene_expression (expression) of BSC-1 in Kidney associated with chronic renal failure

14) Confidence 0.14 Published 2005 Journal Journal of Korean Medical Science Section Body Doc Link PMC2808601 Disease Relevance 1.47 Pain Relevance 0

The decreased AQP2 expression in CRF rats was not altered in response to candesartan treatment; 3) Candesartan treatment was associated with decreased NHE3 and TSC expression in CRF, which could be due to the Ang II AT1 receptor blockade and/or decreased aldosterone levels; and 4) BSC-1 expression was increased in both CRF groups and the increased expression of BSC-1 was more prominent in candesartan-treated CRF rats compared with vehicle-treated CRF rats.

Positive_regulation (increased) of Gene_expression (expression) of BSC-1 associated with chronic renal failure

15) Confidence 0.12 Published 2005 Journal Journal of Korean Medical Science Section Body Doc Link PMC2808601 Disease Relevance 1.20 Pain Relevance 0

Moreover, candesartan treatment in CRF rats significantly increased whole kidney BSC-1 expression (611±126% of sham-operated control level), compared with CRF rats treated with vehicle only (289±63% of sham-operated control level, p<0.05, Fig. 4, Table 2).

Positive_regulation (increased) of Gene_expression (expression) of BSC-1 in kidney associated with chronic renal failure

16) Confidence 0.12 Published 2005 Journal Journal of Korean Medical Science Section Body Doc Link PMC2808601 Disease Relevance 1.42 Pain Relevance 0

We have previously demonstrated that chronic infusion of supraphysiological doses of AngII in normal rats was associated with significantly increased abundance and apical expression level of the Na-H exchanger NHE3 and Na-K-2Cl cotransporter BSC-1 in medullary thick ascending limbs (mTAL), whereas Na,K-ATPase and electroneutral Na-HCO3 cotransporter (NBCn1) levels remained unchanged (10).

Positive_regulation (increased) of Gene_expression (expression) of BSC-1 in ascending limbs

17) Confidence 0.09 Published 2005 Journal Journal of Korean Medical Science Section Body Doc Link PMC2808601 Disease Relevance 0.32 Pain Relevance 0

Moreover, candesartan treatment potentiated the upregulation of BSC-1 protein expression in CRF rats, and this is also compatible with the view that BSC-1 expression is regulated by the prolonged increase in the NaCl load delivered to the TAL due to both hyperfiltration and altered expression in the proximal tubule sodium transporters in remnant kidneys.

Positive_regulation (upregulation) of Gene_expression (expression) of BSC-1 in proximal associated with chronic renal failure

18) Confidence 0.09 Published 2005 Journal Journal of Korean Medical Science Section Body Doc Link PMC2808601 Disease Relevance 0.22 Pain Relevance 0

Semiquantitative immunoblotting demonstrated decreased AQP2 expression in both CRF-C (54% of control levels) and CRF-V (57%), whereas BSC-1 expression was increased in both CRF groups.

Positive_regulation (increased) of Gene_expression (expression) of BSC-1 associated with chronic renal failure

19) Confidence 0.09 Published 2005 Journal Journal of Korean Medical Science Section Abstract Doc Link PMC2808601 Disease Relevance 1.92 Pain Relevance 0

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