Abstract WP269: New Insights Into Worsened Cerebral Ischemia in Hypertensive Rats: Roles of WNK-SPAK/OSR1-NKCC1 Signaling
Bibliographic record
Abstract
Background and Purpose: WNK kinases [with-no-lysine (K)], Ste20-related proline alanine-rich kinase (SPAK) and oxidative stress-responsive kinase-1 (OSR1) are a family of evolutionarily conserved regulators of ion transporter proteins. The kinases alter the phosphorylation state of ion transporter proteins and so play an important role in renal salt handling and in the pathogenesis of hypertension. We previously reported that pharmacological inhibition or genetic knockout of Na+-K+-2Cl- cotransporter 1 (NKCC1) is neuroprotective against ischemic injury. Our current study investigated whether WNK-SPAK/OSR1-NKCC1 signaling is augmented in cerebral ischemia in hypertension. Methods: Cerebral ischemia was induced in adult male Wistar Kyoto (WKY) or spontaneously hypertensive rats (SHR) by 2-hour occlusion of the left middle cerebral artery (MCAO) followed by reperfusion. Brain tissues were harvested for immunoblot assessment of expression levels of NKCC1, SPAK/OSR1 or WNK1-4. Another two cohorts of WKY and SHR were treated with saline or NKCC1 inhibitor bumetanide (BMT, 10 mg/kg/day, i.p.) after MCAO. In these animals, ischemic infarct volume was determined by TTC staining and behavioral deficits were analyzed by neurological scoring and turning-alley test. Results: Basal levels of total NKCC1 protein were significantly higher in the contralateral (CL) cortical tissues in SHR brains than WKY brains. Ischemia was associated with increased phosphorylation of NKCC1 in the ipsilateral (IL) cortex of SHR, but not WKY at 6 hours post-ischemia. WNK1 increased 6.1±1.5 fold and WNK4 increased 8.7±1.7 fold in IL cortex of SHR, but not in that of WKY, and phosphorylated SPAK/OSR1 was unchanged. Lastly, sensitivity to pharmacological NKCC1 inhibition was higher in SHR than WKY rats. BMT blunted the MCAO-induced infarction and improved neurobehavioral score and sensory motor function in SHR rats. Conclusion: These findings suggest that augmented WNK1/4-NKCC1 signaling is responsible, at least in part, for the increased susceptibility to ischemic brain damage associated with hypertension. They highlight the potential for inhibition of WNK1/4-NKCC1 signaling as part of anti-ischemic stroke therapy. Supported by NIH Grant R01 NS38118 (D Sun).
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".