microRNA (miR)-299a-5p Promotes Apoptosis of Tubular Cells Through Erk5 Inhibition
Bibliographic record
Abstract
Background: Diabetic kidney disease (DKD) is the leading cause of end stage renal failure in North America. Tubular epithelial cell apoptosis was shown to contribute to the pathogenesis of DKD by promoting interstitial fibrosis. The mechanism involves the release of cytokines and growth factors that promote interstitial inflammation and myofibroblast activation, which leads to the increased production and accumulation of extracellular matrix proteins in the interstitium. Previously, we showed that microRNA (miR) 299a-5p promotes the fibrotic response in mesangial cells. Here we studied the role of this miR in regulating tubular apoptosis. Methods: Immortalized human kidney proximal tubular cells (HK2) were treated with high glucose (HG); miR299a-5p was detected by qPCR. HK2 cells were transfected with miR overexpression and inhibition plasmids using Transfectamine reagent. Apoptosis was detected using the Annexin V kit. Immunoblotting and immunohistochemistry were used to assess protein expression. Results: HG increased the expression of miR299a-5p in HK2 cells. A bioinformatics screen of four databases showed that miR299a-5p targets MAP3K2, a protein kinase primarily expressed in the tubules. MAP3K2 is a major activator of extracellular signal-regulated kinase 5 (ERK 5), a known anti-apoptotic and anti-inflammatory kinase. miR299a-5p overexpression reduced the protein expression of MAP3K2 and phosphorylation of ERK5, while augmenting the expression of apoptotic markers and endoplasmic reticulum stress in response to HG. Conversely, miR299a-5p inhibition restored MAP3K2 expression and ERK5phosphorylation to basal levels, while attenuating HG-induced apoptosis. In type-1 diabetic Akita mice overexpressing TGFβ1, a model which accelerates DKD, miR299a was increased in association with reduced expression of MAP3K2 and phosphorylated ERK5. Conclusions: These data support an important role for miR299a-5p in regulating tubular cell apoptosis in HG. Future studies will determine whether inhibition of this miR in vivo attenuates apoptosis and reduces tubulointerstitial fibrosis in DKD. We will also explore whether ERK5 phosphorylation may be a potential therapeutic for interstitial fibrosis. Funding: Government Support - Non-U.S.
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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 | 0.001 |
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".