| Full text | |
| Author(s): |
Goncalves, Janaina Garcia
[1]
;
Canale, Daniele
[1]
;
de Braganca, Ana Carolina
[2]
;
Seguro, Antonio Carlos
[2]
;
Shimizu, Maria Heloisa Massola
[1]
;
Volpini, Rildo Aparecido
[2]
Total Authors: 6
|
| Affiliation: | [1] Univ Sao Paulo, Fac Med, Lab Invest Med 12, Sao Paulo - Brazil
[2] Univ Sao Paulo, Hosp Clin HCFMUSP, Fac Med, Lab Invest Med 12, Sao Paulo - Brazil
Total Affiliations: 2
|
| Document type: | Journal article |
| Source: | FRONTIERS IN MEDICINE; v. 7, JAN 5 2021. |
| Web of Science Citations: | 0 |
| Abstract | |
Chronic kidney disease (CKD) has been considered a major public health issue. In addition to cardiovascular diseases and infections, hypovitaminosis D has been considered a non-traditional aggravating factor for CKD progression. Interstitial fibrosis is a hallmark of CKD strongly correlated with deterioration of renal function. Transforming growth factor beta (TGF-beta) is the major regulatory profibrotic cytokine in CKD. Many injurious stimuli converge on the TGF-beta pathway, which has context-dependent pleiotropic effects and interacts with several related renal fibrosis formation (RFF) pathways. Epidermal growth factor receptor (EGFR) is critically involved in CKD progression, exerting a pathogenic role in RFF associated with TGF-beta-related fibrogenesis. Among others, EGFR pathway can be activated by a disintegrin and a metalloproteinase known as tumor necrosis factor alpha-converting enzyme (TACE). Currently no effective therapy is available to completely arrest RFF and slow the progression of CKD. Therefore, we investigated the effects of a double treatment with losartan potassium (L), an AT1R antagonist, and the tyrosine kinase inhibitor erlotinib (E) on the alternative pathway of RFF related to TACE-dependent EGFR activation in 5/6-nephrectomized rats under vitamin D deficiency (D). During the 90-day protocol, male Wistar rats under D, were submitted to 5/6 nephrectomy (N) on day 30 and randomized into four groups: N+D, no treatment; N+D+L, received losartan (50 mg/kg/day); N+D+E, received erlotinib (6 mg/kg/day); N+D+L+E received losartan+erlotinib treatment. N+D+L+E data demonstrated that the double treatment with losartan+erlotinib not only blocked the TACE-dependent EGF receptor activation but also prevented the expression of TGF-beta, protecting against RFF. This renoprotection by losartan+erlotinib was corroborated by a lower expression of ECM proteins and markers of phenotypic alteration as well as a lesser inflammatory cell infiltrate. Although erlotinib alone has been emerging as a renoprotective drug, its association with losartan should be considered as a potential therapeutic strategy on the modulation of RFF. (AU) | |
| FAPESP's process: | 15/05513-1 - Evaluation of the events involved in the renal changes associated with experimental models of ischemic acute kidney injury, 5/6 nephrectomy and nephrotoxicity by Amphotericin B: influence of vitamin D deficiency |
| Grantee: | Rildo Aparecido Volpini |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 18/12297-1 - Analysis of alternative events involved in the formation of renal fibrosis in vitamin D deficient rats submitted to nephrectomy 5/6 |
| Grantee: | Rildo Aparecido Volpini |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 18/04930-6 - Study of vitamin D replacement in the evolution of ischemic acute kidney injury in vitamin D deficient rats |
| Grantee: | Ana Carolina de Bragança Viciana |
| Support Opportunities: | Regular Research Grants |