Journal
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
Volume 1865, Issue 9, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.bbagen.2021.129950
Keywords
Angiotensin II; Albuminuria; Albumin endocytosis; Megalin; Tubule-interstitial injury; Renal disease
Categories
Funding
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [304682/2015-2, 303793/2015-5]
- Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro-FAPERJ [E-26/202.950/2016, E-26/202.833/2017]
- Rio Network of Innovation in Nanosystems for Health (Nanohealth/FAPERJ) [E-26/010.000983/2019]
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The study found that the anti-proteinuric effect of losartan may be associated with modulating albumin endocytosis in PT epithelial cells. The research demonstrates that PT megalin-mediated albumin endocytosis could be a potential target for ARB treatment in renal diseases patients. These results represent a significant advancement in understanding the role of ARBs in treating renal diseases.
Background: Tubule-interstitial injury (TII) is one of the mechanisms involved in the progression of renal diseases with progressive proteinuria. Angiotensin II (Ang II) type 1 receptor blockers (ARBs) have been successfully used to treat renal diseases. However, the mechanism correlating treatment with ARBs and proteinuria is not completely understood. The hypothesis that the anti-proteinuric effect of losartan is associated with the modulation of albumin endocytosis in PT epithelial cells (PTECs) was assessed. Methods: We used a subclinical acute kidney injury animal model (subAKI) and LLC-PK1 cells, a model of PTECs. Results: In subAKI, PT albumin overload induced TII development, measured by: (1) increase in urinary lactate dehydrogenase and gamma-glutamyltranspeptidase activity; (2) proteinuria associated with impairment in megalin-mediated albumin reabsorption; (3) increase in luminal and interstitial space in tubular cortical segments. These effects were avoided by treating the animals with losartan, an ARB. Using LLC-PK1 cells, we observed that: (1) 20 mg/mL albumin increased the secretion of Ang II and decreased megalin-mediated albumin endocytosis; (2) the effects of Ang II and albumin were abolished by 10(-8) M losartan; (3) MEK/ERK pathway is the molecular mechanism underlying the Ang II-mediated inhibitory effect of albumin on PT albumin endocytosis. Conclusion: Our results show that PT megalin-mediated albumin endocytosis is a possible target during the treatment of renal diseases patients with ARB. General significance: The findings obtained in the present work represents a step forward to the current knowledge on about the role of ARBs in the treatment of renal disease.
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