ESR5: Receptor-mediated endocytosis: from GWAS to risk of Chronic Kidney Disease

Supervisor: Olivier Devuyst

PhD Student: Larissa Govers

Short Summary

The overall aim of this project will be to understand the biological basis of the association of common variants in LRP2 and CUBNwith the risk of CKD. The epithelial cells lining the proximal tubules (PT) of the kidney are characterized by a high receptor-mediated endocytosis, mediated by the multiligand receptors megalin and cubilin. These receptors mediate the uptake and processing of low-molecular-weight proteins that are filtered by the glomerulus. The uptake activity mediated by megalin and cubilin is important for hormone homeostasis and conservation of essential vitamins, the clearance of some drugs, and the composition of final urine. GWASs have recently associated common variants in megalin (LRP2) and cubulin (CUBN) genes with the risk of CKD in the general population. Furthermore, variants in CUBN are associated with albuminuria, a major risk factor for CKD and cardiovascular disease. The biological basis of these associations, their potential effect on the endocytic uptake and the biology of PT cells, and the mechanistic link with the risk of CKD are unknown. ESR5 will combine genomic and transcriptomic studies, biochemical studies, mouse and cellular models, human cohorts, and large-scale human population studies. These studies will benefit from the development of a primary culture system of polarized cells obtained from micro-dissected PT segments from the relevant mouse models. The possible benefit of pharmacological compounds interfering with receptor-mediated endocytosis and/or lysosomal processing will be investigated in vitro and in vivo.

Scientific strategy

Expected Results:

  1. Effect of the top GWAS variants on megalin and cubilin expression and function;
  2. Defining the role of receptor-mediated endocytosis in PT dysfunction;
  3. Elucidating mechanisms linking megalin - cubilin with the risk of CKD;
  4. Validation of pathways and biomarkers studies in prospective human cohorts.

Scientific risks and solutions:

These investigations are based on populations studies (e.g. CKDGen), cell systems and mouse lines already used in the hosting Lab, and on a set of robust preliminary data. The group has specific assays and biomarkers to assess receptor-mediated endocytosis. We have access to a large biobank of human material (general population cohorts, CKD cohorts, kidney biopsies from patients with various disorders linked to receptor-mediated endocytosis).