Abstract: TH-PO479
The Association Losartan/Erlotinib Is More Effective in Attenuating Renal Fibrosis Formation by Blocking TACE-Dependent EGF Receptor Activation in 5/6-Nephrectomized Rats Under Vitamin D Deficiency
Session Information
- CKD: Mechanisms - I
November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Volpini, Rildo A., Faculty of Medicine - University of Sao Paulo, São Paulo, São Paulo, Brazil
- de Braganca, Ana Carolina, Faculty of Medicine - University of Sao Paulo, São Paulo, São Paulo, Brazil
- Canale, Daniele, Faculty of Medicine - University of Sao Paulo, São Paulo, São Paulo, Brazil
- Santos, Michele Santiago dos, Faculty of Medicine - University of Sao Paulo, São Paulo, São Paulo, Brazil
- Shimizu, Maria HM, Faculty of Medicine - University of Sao Paulo, São Paulo, São Paulo, Brazil
- Seguro, Antonio C., Faculty of Medicine - University of Sao Paulo, São Paulo, São Paulo, Brazil
- Goncalves, Janaina Garcia, Faculty of Medicine - University of Sao Paulo, São Paulo, São Paulo, Brazil
Background
Hypovitaminosis D has been described as a risk factor for the progression of kidney disease. Among others, overactivity of renin-angiotensin system and renal fibrosis formation (RFF) are hallmarks of CKD. In an alternative RFF pathway, angiotensin II can mediate the activation of tumor necrosis factor-α converting enzyme (TACE), leading to release of TGF-α, which binds to and activates the epidermal growth factor (EGF) receptor (EGFr). Although many studies have focused on the mechanisms underlying RFF, novel anti-fibrotic therapies need to be evaluated in order to retard the progression of CKD. We evaluated the effects of losartan (L) and erlotinib [EGFr inhibitor (E)] in 5/6-nephrectomized rats under vitamin D deficiency.
Methods
Male Wistar rats were fed a vitamin D-free diet (D) for 90 days and submitted to 5/6 Nx (N) on day 30. We studied four groups: DN; DNE (6 mg/Kg/day IP for 53 days); DNL (50 mg/Kg/day in water for 53 days); DNEL (dual treatment). We performed immunohistochemistry for TACE, TGF-α, fibronectin, vimentin and α-SM-actin; ELISA in renal tissue for EGF and collagen 3 (col3); and immunoblot for p-EGFr.
Results
The dual treatment was more effective in blocking the TACE-dependent EGFr activation pathway demonstrated by lower expression of TACE, TGF-α, EGF and p-EGFr. In addition, we observed decreased expression of fibronectin, col3, vimentin and α-SM-actin in renal tissue.
Conclusion
Our results indicate that the dual treatment L+E may represent a novel anti-fibrotic strategy for attenuating CKD. Financial support: FAPESP 2018/12297-1, 2018/04930-6; CNPq 302599/2018-5.
Table 1
| DN | DNE | DNL | DNEL | |
| TACE (%) | 3.98±0.54 | 2.49±0.24c | 2.82±0.29c | 1.37±0.17afi |
| TGF-α (%) | 3.07±0.43 | 1.62±0.34a | 0.84±0.15af | 0.20±0.04adi |
| p-EGF receptor (%) | 100.0±2.0 | 88.0±4.0c | 71.0±3.0ad | 59.0±3.0adi |
| EGF (pg/μg protein) | 2.13±0.18 | 1.59±0.24 | 1.44±0.28 | 1.06±0.07b |
| Fibronectin (%) | 7.41±0.50 | 3.33±0.15a | 3.67±0.32a | 2.49±0.14afi |
| Collagen 3 (ng/μg protein) | 6.37±0.31 | 5.62±0.21 | 4.98±0.41b | 3.82±0.26aei |
| Vimentin (%) | 3.86±0.30 | 2.73±0.23b | 3.26±0.23 | 1.95±0.15afg |
| α-actin (%) | 4.09±0.29 | 2.71±0.21a | 2.33±0.15a | 1.19±0.07adg |
Data are expressed as mean±SEM. a p<0.001, b p<0.01, c p<0.05 vs DN; d p<0.001, e p<0.01, f p<0.05 vs DNE; g p<0.001, i p<0.01 vs DNL.
Funding
- Government Support - Non-U.S.