Abstract 023: Collecting Duct (Pro)Renin Receptor Mediates Angiotensin II-induced Hypertension
Bibliographic record
Abstract
Within the kidney, (pro)renin receptor (PRR) is predominantly expressed in the intercalated cells (IC) of collecting duct (CD) where its expression is induced by angiotensin II (AngII). Here we examined the function of PRR in the CD by analyzing mice with CD-specific deletion of PRR (CD PRR KO) using AQP2-Cre which has recently been shown to target both IC and principal cells (PC). Radiotelemetry demonstrated that the null mice were largely resistant to AngII-induced hypertension (MAP on day 7: Floxed/AngII 137.4 ± 3.5 vs. KO/AngII 121.2 ± 1.1 mmHg, p<0.05, n=4), accompanied with reduced urinary soluble PRR (sPRR) and aldosterone levels. Electrophysiology analysis demonstrated that within minutes activation of PRR by 10 nM prorenin induced a transient increase in amiloride-sensitive Na+ transport in cultured mpkCCD cells (Ieq: 1.85 ± 0.17 vs. 1.30 ± 0.06 μA/cm2, p<0.05). Interestingly, this was followed by a second phase of ENaC activation after 6 h, which reached the plateau activation at 24 h, accompanied with increased aldosterone release as assessed by ELISA (14.41 ± 0.92 vs. 5.45 ± 0.28 pg/ ml/μg protein, p<0.05). The chronic but not acute phase of ENaC activation was abolished by eplerenone. Both phases of ENaC activation depended on Nox4-derived reactive oxygen species (ROS). Immunostaining using an antibody against sPRR (the N terminus) showed exclusive labeling in the principle cells (PC) whereas the labeling with the C-terminal antibody was exclusively found in IC. A recombinant histidine-tagged sPRR, termed sPRR-His, in the nanomolar range induced a similar dual effect on ENaC activation as prorenin. Intravenous infusion of sPRR-His in CD PRR KO mice for 5 days completely restored the hypertensive response to AngII (MAP: 135.5 ± 7.5 vs. 116.7 ± 5.7 mmHg, p<0.05). We conclude that: 1) CD PRR mediates AngII-induced hypertension; 2) PRR activation in the CD leads to increased ENaC activity acutely through the direct action of ROS and chronically through local generation of aldosterone; 3) sPRR derived from IC may act in a paracrine fashion to stimulate Na+ transport in PC.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.008 | 0.004 |
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 source (direct Gemma or distilled Codex), 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".