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Kidney Week

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
 DNDNEDNLDNEL
TACE (%)3.98±0.542.49±0.24c2.82±0.29c1.37±0.17afi
TGF-α (%)3.07±0.431.62±0.34a0.84±0.15af0.20±0.04adi
p-EGF receptor (%)100.0±2.088.0±4.0c71.0±3.0ad59.0±3.0adi
EGF (pg/μg protein)2.13±0.181.59±0.241.44±0.281.06±0.07b
Fibronectin (%)7.41±0.503.33±0.15a3.67±0.32a2.49±0.14afi
Collagen 3 (ng/μg protein)6.37±0.315.62±0.214.98±0.41b3.82±0.26aei
Vimentin (%)3.86±0.302.73±0.23b3.26±0.231.95±0.15afg
α-actin (%)4.09±0.292.71±0.21a2.33±0.15a1.19±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.