Abstract: FR-PO138
The Dual Blockade Losartan/Erlotinib Attenuates Inflammation and Fibrosis Formation in Vitamin D Deficiency Rats Submitted to 5/6 Nephrectomy
Session Information
- Molecular Mechanisms of CKD - II
October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 1903 CKD (Non-Dialysis): Mechanisms
Authors
- Goncalves, Janaina Garcia, Faculty of Medicine - University of Sao Paulo, Sao Paulo, Sao Paulo, Brazil
- de Braganca, Ana Carolina, Faculty of Medicine - University of Sao Paulo, Sao Paulo, Sao Paulo, Brazil
- Canale, Daniele, Faculty of Medicine - University of Sao Paulo, Sao Paulo, Sao Paulo, Brazil
- Shimizu, Maria HM, Faculty of Medicine - University of Sao Paulo, Sao Paulo, Sao Paulo, Brazil
- Seguro, Antonio C., Faculty of Medicine - University of Sao Paulo, Sao Paulo, Sao Paulo, Brazil
- Volpini, Rildo A., Faculty of Medicine - University of Sao Paulo, Sao Paulo, Sao Paulo, Brazil
Background
5/6 nephrectomy (N) is a classical experimental model of chronic kidney disease (CKD). Some studies have been linking vitamin D deficiency (VDD) to inflammatory process and renal fibrosis formation (RFF). Besides the beneficial effects of AII type I receptor antagonists, many efforts have been made to investigate alternative pathways related to RFF and inflammation. We evaluated the effects of the dual blockade including losartan (L) and erlotinib (E), an inhibitor of the epidermal growth factor receptor (EGFr) activity on CKD in rats under VDD.
Methods
Male Wistar rats received a vitamin D free (D) diet for 90 days. On day 30, rats were submitted to N surgery. Four groups were studied: D+N; D+N+L (50 mg/Kg/day in drinking water for 53 days); D+N+E (6 mg/Kg/day intraperitoneally for 53 days); D+N+L+E (dual treatment). We measured serum levels of 25(OH)D and aldosterone by ELISA; inulin clearance (Cin); mean arterial pressure (MAP); proteinuria; immunoblotted for TGF-β1, TGF-α and p-EGFr; performed IHC for CD206 and CD68; and evaluated interstitium enlargement by fraction interstitial area (FIA).
Results
All animals had untedectable levels of 25(OH)D. L+E treatment improved renal function and decreased MAP and proteinuria. L+E treatment reduced the expression of TGF-β1, TGF-α and p-EGFr, attenuating the expansion of FIA. Also, L+E mitigated the inflammatory profile of macrophages.
Conclusion
The dual blockade L+E ameliorated the course of CKD by retarding RFF and modulating the inflammatory phenotype of macrophages. (FAPESP 2015/05513-1; 2015/11933-3)
| N+D | N+D+L | N+D+E | N+D+L+E | |
| Cin (mL/min/100g BW) | 0.39±0.02 | 0.63±0.04a | 0.50±0.03 | 0.60±0.04b |
| MAP (mmHg) | 163±4 | 108±2a | 147±4cd | 107±3ag |
| Aldosterone (pg/mL) | 3692±390 | 1496±319a | 3266±644f | 1650±252bi |
| Proteinuria (mL/24 h) | 24.5±2.7 | 13.8±1.3a | 15.8±1.5a | 11.5±0.7a |
| TGF-β1 (%) | 100±3 | 32±3a | 33±9a | 36±6a |
| TGF-α (%) | 100±6 | 33±4a | 33±9a | 36±6a |
| p-EGFr (%) | 100±2 | 71±3a | 88±4cd | 59±3afg |
| FIA (%) | 22.5±0.5 | 13.1±0.8a | 14.7±0.9a | 10.4±0.4aeg |
| M2 macrophages - CD206+ (%) | 0.11±0.01 | 0.32±0.02c | 0.30±0.04b | 0.41±0.05a |
| M1+M2 macrophages - CD68+ (%) | 0.94±0.05 | 0.75±0.03c | 0.69±0.04c | 0.60±0.06a |
Data are expressed as mean±SEM. BW, Body weight. a p<0.001, b p<0.01, c p<0.05 vs N+D; d p <0.001, e p<0.01, f p<0.05 vs. N+D+L; g p<0.001, i p<0.05 vs N+D+E.
Funding
- Government Support - Non-U.S.