Abstract 40: Renin is Produced By a General Lysosomal Degradation Mechanism
Bibliographic record
Abstract
Renin is secreted almost exclusively by the juxtaglomerular (JG) cells of the kidney where it is first made as an inactive precursor called prorenin. Conversion of prorenin to active renin requires the proteolytic removal of an N-terminal prosegment by a second protease whose identity is still debated. Active renin is then stored in dense vesicles and secreted in response to stimuli. Using confocal microscopy we found that C57BL6 mouse kidney JG cells are highly enriched in Lamp-1, a biomarker for lysosomes, and that renin and Lamp-1 co-localize in renin storage vesicles. These data suggest that renin is stored in secretory lysosomes. N-terminal sequencing of C57BL6 mouse Ren-1 renin purified from kidney revealed an N-terminus beginning with SPVVLT¼. This is the same amino terminus as that reported for rat renin and mouse As4.1 cells and different from that reported for human renin. This result raises the possibility that rodents and humans use different prorenin processing enzymes (PPE). Treatment of mice with captopril for 7 days increases plasma active renin by 19-fold (control 149 +/- 22 vs. treated 2859 +/- 672 ng AI/ml/hr, P< 0.0001) and kidney renin messenger RNA by 4.81-fold (P< 0.0001). Nevertheless, Illumina expression array analysis of C57BL6 mouse kidney before and after captopril treatment did not reveal candidate PPEs whose expression paralleled that of renin. This result suggests that the PPE is not limited to JG cells. To test the possibility that general lysosomal hydrolases are responsible for renin production, we used a Lamp-1 C-terminal sequence to force the sorting of mouse Ren-1 prorenin into lysosomes of transfected human embryonic kidney (HEK) cells. Transfection resulted in the intracellular retention of renin of the appropriate molecular weight and which lacked the engineered Lamp-1 C-terminal tail, suggesting that the proteolytic processing of prorenin is not carried out by a protease that is restricted to JG cells. Altogether, our results are consistent with mature renin being produced by lysosomal degradation of the prosegment and the selective resistance of mature renin to hydrolysis. The different N-termini of rodent and human renins could be explained by differential susceptibility of their prosegments to lysosomal hydrolysis.
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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 | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.009 | 0.006 |
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".