Abstract: FR-PO328
Diet Modification to Drive Fibrotic Response in Diabetic Kidney Disease (DKD) Model
Session Information
- Diabetic Kidney Disease: Basic - I
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Cavanaugh, Cassandre, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Hinke, Simon A., Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Rankin, Matthew M., Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Meng, Rong, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Shukla, Neetu, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
- Nawrocki, Andrea R., Janssen Research and Development LLC, Spring House, Pennsylvania, United States
Group or Team Name
- CVMR & PH Discovery In Vivo Pharmacology.
Background
Diabetes is a major cause of chronic kidney disease, affecting approximately 25% of diabetic patients. Several rodent models of Diabetic Kidney Disease (DKD) have been developed; however, drug discovery is hampered by the lack of preclinical rodent models with clinically relevant urinary albuminuria creatinine ratio (UACR) and/or histological fibrosis observed in humans. Here we sought to develop a new translational mouse DKD model incorporating streptozotocin (STZ)-induced hyperglycemia, mild hypertension from nitric oxide synthase inhibition, and dietary modification to drive the fibrotic response, on top of a uninephrectomized (UNx)/hyperfiltration phenotype.
Methods
UNx Male 129S1 mice (Jackson Labs) were uninephrectomized at 7 weeks old and given STZ injections (5-40mg/kg IP) to induce diabetes. Trimethylamine n-oxide (TMAO) and Choline formulated in D12450J low fat diet (LFD) and D12492 high fat diet (HFD) for rodents (Research Diets). 100mg/L nitroarginine (L-NNA) provided in drinking water. Body weight, food intake and fed blood glucose collected weekly and urine collected biweekly for 8 weeks. At the end of treatment, animals euthanized, kidneys collected for collagen and histological analysis. Terminal plasma analyzed for blood chemistry, TMAO and circulating dietary precursors of TMAO.
Results
STZ-induced hyperglycemia confirmed in the mice (396.3±3.6mg/dL). Daily TMAO and choline intake, both LFD and HFD diet admixtures were similar (Choline: LFD 166.9±7.6g/kg; HFD 178.4±4.6g/kg; TMAO: LFD 54.1±1.8g/kg; HFD 65.2±2.6g/kg). Betaine, Carnitine and Choline dietary TMAO precursors increased in both LFD and HFD choline admixtures. TMAO did not significantly change any dietary precursor levels compared to control. UACR significantly increased after 8 weeks in both Choline supplemented, LFD (p=0.0024; 72.4±13.6) and HFD (p=0.0472; 59.7±8.2). The primary histological lesion observed was tubulointerstitial collagen thickening, seen in LFD TMAO & Choline, and HFD Choline groups.
Conclusion
Refinement of a hypertensive, diabetic, hyperfiltering mouse kidney disease model using dietary supplements to increase renal fibrosis observed to achieve comparable kidney functional impairment to that of human DKD patients, with some evidence of histological damage. This animal model may be used to assess preclinical efficacy of investigational therapies for DKD.
Funding
- Commercial Support – Janssen R&D Pharmaceutical Companies of J&J