Abstract: PO0943
Therapeutic Benefit of CCR2 Antagonism in a Model of Diabetic Nephropathy Suggests a Mechanism of Action Distinct from Nrf2 Activation
Session Information
- Diabetic Kidney Disease: New Pathways and Therapies
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Miao, Zhenhua, ChemoCentryx, Inc, Mountain View, California, United States
- Zhao, Bin N., ChemoCentryx, Inc, Mountain View, California, United States
- Ertl, Linda, ChemoCentryx, Inc, Mountain View, California, United States
- Chhina, Vicky, ChemoCentryx, Inc, Mountain View, California, United States
- Kumamoto, Alice Liu, ChemoCentryx, Inc, Mountain View, California, United States
- Dang, Ton Hy, ChemoCentryx, Inc, Mountain View, California, United States
- Yau, Simon Kwok-Pan, ChemoCentryx, Inc, Mountain View, California, United States
- Luong, Kenken, ChemoCentryx, Inc, Mountain View, California, United States
- Zhang, Penglie, ChemoCentryx, Inc, Mountain View, California, United States
- Sullivan, Kathleen M., ChemoCentryx, Inc, Mountain View, California, United States
- Charo, Israel, ChemoCentryx, Inc, Mountain View, California, United States
- Schall, Thomas J., ChemoCentryx, Inc, Mountain View, California, United States
Background
Diabetic nephropathy (DN) affects nearly half of the patients with type 2 diabetes and is characterized by albuminuria and/or a relentless decline in renal function that may lead to ESRD. We have recently shown that a CCR2 antagonist improved renal structure and reduced proteinuria in the db/db murine model of DN, as well as in the Adriamycin and 5/6 nephrectomy models of CKD. To understand the mechanism we compared CCX872, a small molecule antagonist of CCR2, with Bardoxolone methyl, an investigational drug targeting Nrf2 pathway in the db/db murine model of DN.
Methods
The [KS1] CCR2 specific inhibitor CCX872 and Nrf2 activator Bardoxolone methyl were formulated in 1 % HPMC and dosed for 2 weeks. Proteinuria (urinary albumin excretion rate- UAER) and glomerular filtration rate (GFR) were assessed by measuring murine albumin ELISA and FITC-insulin, respectively. The kidneys were disrupted non-enzymatically, and preparations enriched in glomerular cells were obtained by filtration. Activated parietal epithelial cells (PECs) were analyzed in these preparations by flow cytometry.
Results
UAER was rapidly and significantly reduced after treatment with CCX872: 59% (p=0.004 ) and 76% (p<0.0001), versus vehicle by week 1 and 2 respectively. In contrast, Bardoxolone did not improve UAER. The db/db mice had kidney hyperfiltration, which measured 943 µl/min at 8 weeks. Bardoxolone reduced hyperfiltration in db/db mice by 36% versus vehicle at week 2, while CCX872 had no effect on GFR. Furthermore, CCX872 significantly reduced the number of CD44 positive activated PECs in the glomerular cell preparations(p=0.04), while Bardoxolone had no effect on the number of these cells.
Conclusion
Treatment with CCR2 antagonist provides rapid renal protection in the db/db mice, as measured by improved UAER. The reduction in UAER was associated with reduction of activated PECs, which are known to contribute to kidney disease. Although Bardoxolone was able to improve GFP, it did not improve UAER or reduce the number of activated PECs. Thus, CCR2 blockade and Nrf2 activation appear to afford renal protection by different mechanisms in the db/db model of DN.