The podocyte protease web: uncovering the gatekeepers of glomerular disease

Proteases regulate glomerular physiology. The last decade has revealed a multitude of podocyte proteases that govern the glomerular response to numerous chemical, mechanical, and metabolic cues. These proteases form a protein signaling web that integrates stress stimuli and serves as a key controller of the glomerular microenvironment. Both the extracellular and intracellular proteolytic networks are perturbed in focal segmental glomerulosclerosis, as well as hypertensive and diabetic nephropathy. Accordingly, the highly intertwined podocyte protease web is an integrative part of the podocyte's damage response. Novel mass spectrometry-based technologies will help to untangle this proteolytic network: functional readouts acquired from deep podocyte proteomics, single glomerular proteomics, and degradomics have exposed unanticipated protease activity in podocytes. Future efforts should characterize the interdependency and upstream regulation of key proteases, along with their role in promoting tissue heterogeneity in glomerular diseases. These efforts will not only illuminate the machinery of podocyte proteostasis but also reveal avenues for therapeutic intervention in the podocyte protease web.