Project Details
Projekt
Cell-non-autonomous control of kidney podocyte proteostasis
Applicant
Professor Dr. Thomas Benzing
Subject Area
Cell Biology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 531902955
Kidney function depends on the bulk filtration of large volumes of water and small solutes to clear potential toxins derived from intracellular metabolism and gastrointestinal microbial metabolism while maintaining salt, water, and acid-base homeostasis (Benzing, Salant (2021) N Engl J Med 384, 1437-1446). About a million filtration units in the kidneys, called glomeruli, produce as much as 180 liters of filtrate from plasma per day in healthy adults, yet only very small amounts of plasma protein leak into the urine. The essential cells for this enormous filtration capacity are podocytes, which are highly differentiated, postmitotic epithelial cells. Blood pressure and massive fluid filtration expose podocytes to enormous physical forces. Moreover, podocytes are challenged by bathing in urine devoid of sufficient oxygen and rich in filtered toxic waste products. Tightly controlled signaling networks maintain structure and function, preserving their delicate architecture required for proper kidney function. Most kidney diseases that progress to chronic kidney disease (CKD) start in the glomeruli due to the limited ability of podocytes for self-renewal. As these cells do not divide, they must maintain a healthy proteome for the organism’s lifetime. Podocyte proteostasis mechanisms are central to maintaining kidney health. Interfering with proteasomal degradation of podocyte proteins causes kidney disease. Moreover, the deregulated autophagy of these highly autophagic cells contributes to diabetic kidney disease. While cell-autonomous quality control mechanisms have been extensively studied, little is known about cell-non-autonomous proteostasis control, particularly how the immune system may alter podocyte proteostasis to cause disease. Recent experimental and clinical evidence showed that immune cells can interfere with podocyte protein homeostasis without infiltrating the podocyte microenvironment. Immune cell mediators can cause deregulated podocyte autophagy and alter ubiquitylation and degradation of podocyte protein complexes. Autoantibodies can bind to the slit diaphragm, a specialized cell junction with a signaling function that connects podocyte processes and forms the filtration slit. Binding causes nephrin phosphorylation, cytoskeletal rearrangements, and degradation of the slit diaphragm protein complex. Here, we will harness the expertise and power of interactions within this Research Unit to investigate cell-non-autonomous control of podocyte proteostasis in immune-mediated minimal change disease, a particular role for UBR4 and HUWE1 ubiquitylation complexes, and the role of proteostasis in enhancing kidney health and preventing podocyte dysfunction and structural changes.
DFG Programme
Research Units
