Tubular toxicity of proteinuria in Chronic Kidney Disease

Proteinuria is a major pathological feature of Chronic Kidney Disease (CKD). In the first part of this thesis we used the transgenic POD-ATTAC mouse model of inducible high grade proteinuria as well as kidney epithelial cell lines exposed to albumin to study the mechanisms underlying decreased Klotho expression by albuminuria. We observed downregulation of Klotho mRNA and protein levels with albumin-specific effects. This reduction may be attributed to increased Klotho protein degradation as well as induction of ER stress and potential Klotho gene transcriptional regulation by ATF4 and ATF3. In the second part, we used a tubule-specific knock-out mouse model that we crossed with the POD-ATTAC mice to investigate the potential role of 24p3 receptor in albumin internalization in the distal tubule. Our data suggest that the contribution of 24p3R might be small since no major changes in kidney function or overall inflammatory and fibrotic process were detected