miR299a-5p Is a Novel Mediator of Fibrosis in Diabetic Kidney Disease
Bibliographic record
Abstract
Background: Diabetic kidney disease (DKD) is the leading cause of kidney failure in North America, characterized by glomerular accumulation of extracellular matrix (ECM) proteins. High glucose (HG) induction of glomerular mesangial cell (MC) profibrotic responses, mediated by the cytokines TGFβ1 and activins, plays a central role in its pathogenesis. We recently showed that TGFβ1 upregulation of microRNA (miR) 299a-5p promoted its profibrotic responses in MC. Here we studied the role of this miR in DKD. Methods: Primary mouse MC were treated with HG at 30 mM. miR299a-5p was detected by qPCR or ISH. miR overexpression and inhibition plasmids were transfected by electroporation. TGFβ1 and activin signaling was assessed by activity of their downstream mediator Smad3 using the CAGA12 reporter. ECM production was assessed using immunoblotting and activity of the COL1α1 promoter luciferase reporter. Results: HG increased the expression of miR299a-5p in MC. This was also increased in type 1 Akita diabetic kidneys in both glomeruli and tubules, as assessed by ISH. In MC, miR299a-5p overexpression increased Smad3 activation and COL1α1 promoter activity. Conversely, miR299a-5p inhibition attenuated HG-induced COL1α1 promoter and Smad3 activation, as well as upregulation of ECM proteins. miR299a-5p is predicted to target the TGFβ1 inhibitor Cripto-1 (CR-1), and we previously showed that it targeted the activin inhibitor follistatin (FST). Here we show that HG decreased expression of both CR-1 and FST. This was similarly seen with miR299a-5p overexpression. CR-1 or FST treatment individually attenuated the increased COL1α1 promoter and Smad3 activity seen with miR299a-5p overexpression, and together showed an additive inhibitory effect. Conclusions: These data support an important role for miR299a-5p in regulation of the profibrotic response to HG. Through suppression of two important antifibrotic proteins, CR-1 and FST, miR299a-5p potentiates the action of TGFβ family profibrotic cytokines. Future studies will determine whether inhibition of this miR can attenuate DKD. Funding: Government Support - Non-U.S.
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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 | 0.001 |
| 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 | 0.001 |
| 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".