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Abstract: PO1698

The Role of LRP1 in Podocytes

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Groener, Marwin, University Hospital Erlangen - Department of Medicine 4 - Nephrology and Hypertension, Erlangen, Germany
  • Bolanos-Palmieri, Patricia, University Hospital Erlangen - Department of Medicine 4 - Nephrology and Hypertension, Erlangen, Germany
  • Jobst-Schwan, Tilman, University Hospital Erlangen - Department of Medicine 4 - Nephrology and Hypertension, Erlangen, Germany
  • Schiffer, Mario, University Hospital Erlangen - Department of Medicine 4 - Nephrology and Hypertension, Erlangen, Germany
Background

Recent studies have demonstrated the importance of endocytosis for podocyte health. However, little is known about the function of the internalized cargo proteins. We investigated the role of the low-density lipoprotein receptor-related protein 1 (LRP1), a large endocytic scavenger receptor, in podocytes in vitro and in vivo.

Methods

We used immunoblotting and -fluorescence to determine quantity and localization of LRP1 in cultured human podocytes. siRNA knockdown (KD) of LRP1 and an antagonist were used to investigate potential functional importance in vitro. We used zebrafish morpholino knockdown models of LRP1 homologs to study the function of LRP1 in vivo. LRP1 expression in healthy and diseased human renal tissue was determined by immunohistochemistry.

Results

LRP1 is highly expressed in cultured podocytes where it localizes to the membrane and perinuclear region. It colocalizes with early and late endosomes, in line with its role in endocytic trafficking. Interaction with β1-Integrin (ITB1) was confirmed by immunoprecipitation and colocalization. siRNA KD of LRP1 resulted in a reduction of podocyte number and cell size. Morpholino KD of both Lrp1 isoforms in zebrafish led to pericardial effusion and generalized edema, hinting at a renal phenotype. Interestingly, LRP1 has nearly absent baseline expression in healthy human glomeruli. Glomerular expression is significantly increased in human biopsies of various podocytopathies. However, LRP1 does not colocalize with the podocyte marker nephrin in human tissue.

Conclusion

LRP1 is a highly expressed endocytic receptor in cultured podocytes. Aberrant LRP1 function caused by siRNA KD or pharmacological inhibition resulted in disarrangement of podocyte shape, implicating a crucial role in adhesion and cytoskeletal regulation in vitro. Colocalization and immunoprecipitation with ITB1 suggests involvement in integrin trafficking. The importance of LRP1 for kidney function is corroborated by our zebrafish experiments where Lrp1 silencing led to a renal phenotype. Since glomerular LRP1 expression is increased in proteinuric diseases, it could function as a mediating or compensating factor in glomerular injury. However, its absence from podocytes in vivo makes its function for podocytes outside of the culture environment unclear. Our findings thus exemplify the difference in podocyte adhesion regulation between podocytes in vitro and in vivo.

Funding

  • Private Foundation Support