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

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.

Automated summary

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.