Chronic kidney disease (CKD) is becoming an increasingly prevalent condition affecting almost 10% of the population in Western societies. Most kidney diseases that progress to CKD start in the glomerulus, the renal filtration unit, due to a limited capacity of glomeruli for regeneration and the limited ability of terminally differentiated glomerular podocytes for self-renewal. Podocytes enwrap the glomerular capillaries, and elaborate primary and interdigitating secondary extensions connected by a membrane-like cell junction called the slit diaphragm. Together with the underlying glomerular basement membrane and specialized fenestrated glomerular endothelial cells, podocytes constitute the kidney filter. Over the past decade, we showed that proteins residing at the slit diaphragm form an evolutionarily conserved mechanosensitive multiprotein complex that controls podocyte morphology, viability and function. Recently, our group's super-resolution STED imaging of CRISPR-genetically engineered mouse models of human disease revealed the biophysical basis of glomerular ultrafiltration. These data now explain how podocyte ultrastructural changes may translate into albuminuria: Podocyte ultrastructural simplification and shortening of the slit diaphragm cause loss of buttress forces of podocytes to counteract capillary blood pressure. Diminished buttress forces result in decompression of the GBM and loss of the size-selective barrier. However, the link between cell injury and podocyte ultrastructural changes remains elusive.
Here we will (1) study the role of two evolutionarily conserved ubiquitylation machines containing HUWE1 or Ubr4 and associated proteins in mediating disease-related proteostasis defects that cause ultrastructural failure, and (2) examine the dynamic crosstalk of slit diaphragm and cytoskeletal proteins in glomerular disease in vivo.
Injury to podocytes causes loss of buttress forces, decompression of the GBM, and failure of the glomerular filter. The proposed project will now link podocyte deregulated signaling and altered protein homeostasis with cytoskeletal changes and ultrastructural podocyte alterations. Clinically, this is most relevant as drugs that are able to reduce mechanical strain (such as SGLT2 inhibitors and renin-angiotensin system blockers) have the potential to alleviate disease and prevent end-stage renal failure. Thus, the development of targeted interventions to support podocyte mechanical stability is the most promising therapeutic approach in glomerular disease treatment.
Clinic II of Internal Medicine
CMMC - Chair
CMMC - PI - C 01
Linus Butt, Amrei Mandel