PPARγ-Induced Stimulation of Amiloride-Sensitive Sodium Current in Renal Collecting Duct Principal Cells is Serum and Insulin Dependent
Bibliographic record
Abstract
BACKGROUND/AIMS: Thiazolidinediones (TZDs), such as rosiglitazone or pioglitazone, are peroxisome proliferator-activated receptor gamma (PPARγ) agonists currently used in the treatment of type 2 diabetes. However, their clinical applicability is limited by common and severe side effects including strong water retention, edema and cardiac stroke. The precise mechanisms leading to these disorders are not clearly understood and remain controversial. While the nature of the disorders due to TZDs points to an increase in ENaC-mediated sodium reabsorption in the aldosterone-sensitive distal nephron, some studies suggested that this channel was not targeted by PPARγ agonists. METHODS: Mouse cortical collecting duct cells were incubated in different types of culture medium and treated with or without rosiglitazone. Transepithelial Na(+) current was measured and the changes in SGK and Nedd4 expression were determined by immunoblotting. RESULTS: Herein we demonstrate that rosiglitazone stimulates the amiloride-sensitive transepithelial sodium current in Collecting Duct Principal Cells after 3h and 24h treatment. This activation was dependent of both serum and insulin in culture medium and was mediated by SGK1/Nedd4-2 pathway stimulation. In these conditions, rosiglitazone induced SGK1 expression, Nedd4-2 phosphorylation and thus abolished ubiquitylation and internalization of ENaC channels. This mechanism explains most of the side effects of thiazolidinediones previously observed in humans and animals. CONCLUSION: Our data show an increase in transepithelial sodium amiloride-sensitive current induced by a PPARγ agonist in presence of serum and insulin, thus confirming some in-vitro and in-vivo experiments while providing explanations for previous conflicting findings.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".