MO608: INV-202, A CB1 Receptor Blocker, Reduces Renal Injury in A Murine Model of Streptozotocin (STZ)-Induced Type-1 Diabetes
Bibliographic record
Abstract
Abstract BACKGROUND AND AIMS Renal diseases remain a burden for Public Health and chronic kidney disease (CKD) affects several millions of individuals worldwide. Diabetic Nephropathy (DN) is the most frequent consequence of diabetes and is characterized by an increase in urinary albumin excretion and progressive loss of renal function associated with glomerular basement membrane thickening, mesangial expansion, nodular glomerular sclerosis and tubulointerstitial fibrosis. To date, there are few treatments that can prevent its progression. Indeed, current therapeutic approaches including RAAS blockers, SGLT2 inhibitors or both approaches combined do not fully abrogate DN progression. A growing body of experimental evidence suggests that modulation of the endocannabinoid system, and in particular its type 1 receptor (CB1R), may be a therapeutic tool in the management of CKD and more particularly DN. CB1R blockade represents a potential therapeutic modality in the fight against obesity, diabetes and their metabolic sequelae. In kidney, CB1R inhibition promotes a reduction in albuminuria, renal fibrosis and preserves renal function in both obesity-induced and diabetic nephropathy in mice mainly through a direct action of CB1R in podocytes and/or proximal tubules. INV-202 is a peripherally acting Cannabinoid receptor-1 (CB1r) inverse agonist that is under clinical development for the treatment of diseases associated with diabetes and metabolic syndrome. Here we report the effects of INV-202 on renal function and associated parameters in a preclinical model of diabetic nephropathy. METHOD Twelve weeks after the initiation of diabetes using streptozotocin, C57BL6/J mice (8 per treatment group) were randomized to receive a daily oral dose of INV-202, 0.3 mg/kg and 3 mg/kg or vehicle for 4 weeks. Five mice not treated with STZ were used as a nondiabetic control. At the end of treatment, animals were sacrificed. Urinary albumin-to-creatinine ratio (ACR), renal matrix remodelling, glomerular filtration and interstitial fibrosis were assessed in addition to glucose levels, body weight and organ weights. RESULTS After 28 days of treatment, there was no significant effect on hyperglycemia or body weight with either dose of INV-202. Renal and hepatic weights were reduced while heart weight was unaffected. This remained true when normalizing for tibial length. Compared with vehicle-treated diabetic mice, INV-202-challenged mice displayed a marked decrease in many clinical features of DN such as albuminuria, albumin-to-creatinine ratio, urinary urea, loss of glomerular filtration rate and renal hypertrophy. Interestingly, we also found an improvement in both podocyte and proximal tubular cells morphology and health markers that were likely responsible for the improvement previously mentioned. In addition, INV-202 led to a downregulation of the angiotensin II receptor expression as well as a reduced urinary excretion, suggesting an inhibitory effect of this compound on the angiotensin II-mediated renal dysfunction in the context of DN. Furthermore, INV-202 also led to a drastic reduction in renal inflammation and oxidative stress markers that are known to be highly involved in the pathogenesis of DN. Finally, despite the limitation of our model in regard to interstitial fibrosis development, we could observe a marked anti-fibrotic effect of INV-202. CONCLUSION Treatment with INV-202 reduced the progression of nephropathy in STZ-induced diabetic mice. Improvements in kidney size, function and histology, with corresponding gene expression, were noted with both doses of INV-202. Further work to explore the effect of INV-202 in humans is warranted.
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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 | 0.001 |
| 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 | 0.000 |
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".