TY - JOUR
T1 - Megalin-mediated albumin endocytosis in renal proximal tubules is involved in the antiproteinuric effect of angiotensin II type 1 receptor blocker in a subclinical acute kidney injury animal model
AU - Peruchetti, Diogo B.
AU - Barahuna-Filho, Paulo F.R.
AU - Silva-Aguiar, Rodrigo P.
AU - Abreu, Thiago P.
AU - Takiya, Christina M.
AU - Cheng, Jie
AU - Pinheiro, Ana Acacia S.
AU - Cebotaru, Liudmila
AU - Guggino, William B.
AU - Caruso-Neves, Celso
N1 - Publisher Copyright:
© 2021 Elsevier B.V.
PY - 2021/9
Y1 - 2021/9
N2 - 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 γ-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.
AB - 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 γ-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.
KW - Albumin endocytosis
KW - Albuminuria
KW - Angiotensin II
KW - Megalin
KW - Renal disease
KW - Tubule-interstitial injury
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U2 - 10.1016/j.bbagen.2021.129950
DO - 10.1016/j.bbagen.2021.129950
M3 - Article
C2 - 34144121
AN - SCOPUS:85109078150
SN - 0304-4165
VL - 1865
JO - Biochimica et Biophysica Acta - General Subjects
JF - Biochimica et Biophysica Acta - General Subjects
IS - 9
M1 - 129950
ER -