Deletion of iPLA2γ Protects Mice From Diabetic Nephropathy
Bibliographic record
Abstract
Background: Calcium-independent phospholipase A2γ (iPLA2γ) is localized in glomerular epithelial cells (GECs)/podocytes at the mitochondria and endoplasmic reticulum, and can mediate release of arachidonic acid and prostanoids. Global knockout (KO) of iPLA2γ in mice did not cause albuminuria, but resulted in mitochondrial structural abnormalities and enhanced autophagy in podocytes. In acute glomerulonephritis (GN; anti-glomerular basement membrane GN and adriamycin nephrosis), deletion of iPLA2γ exacerbated albuminuria and podocyte injury. This study addresses the role of iPLA2γ in diabetic nephropathy. Methods: Hyperglycemia was induced in male mice (mean age 6.5 months) with streptozotocin (STZ). Cultured GECs were produced from control and iPLA2γ KO mice; the GECs express synaptopodin and nephrin. Results: STZ induced progressive albuminuria in control (Ctrl) mice (˜5 mg/mg creatinine at 21 weeks), while albuminuria did not increase in iPLA2γ KO mice (˜0.5 mg/mg creatinine), remaining comparable to untreated groups (9-15 mice/group). Despite similar exposure to STZ, the STZ-KO mice developed a lower level of hyperglycemia compared to STZ-Ctrl. However, there was no significant correlation between the degree of hyperglycemia and albuminuria, and even KO mice with greatest hyperglycemia did not develop significant albuminuria. Mortality at 21 weeks was greatest in STZ-Ctrl mice (20%). Sclerotic glomeruli and enlarged glomerular capillary loops were increased significantly in Ctrl-STZ compared to KO-STZ mice. Glomerular LC3-II (a marker of autophagy) was increased in KO and KO-STZ mice compared to respective Ctrl groups. Glomerular matrix was expanded in both Ctrl-STZ and KO-STZ groups. STZ did not alter podocyte number, nor amounts of glomerular synaptopodin, nephrin, podocalyxin, F-actin, and macrophages. Treatment of cultured GECs with H2O2 resulted in increased cell death in Ctrl GECs compared to iPLA2γ KO, and the increase was slightly greater in medium with 18 mM glucose compared to 8 mM. H2O2-induced cell death was not affected by inhibition of prostanoid production with indomethacin. Conclusions: In contrast to acute GN, mice with global deletion of iPLA2γ are protected from developing chronic glomerular injury in diabetic nephropathy. This may be related at least in part to increased glomerular autophagy. Funding: Private Foundation Support, Government Support - Non-U.S.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 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".