Glomerular Regeneration: When Can the Kidney Regenerate from Injury and What Turns Failure into Success

For many years, the glomerulus was considered incapable of regeneration. However, experimental and clinical evidence challenged this concept and showed that glomerular injury and even glomerulosclerosis can undergo regression under certain circumstances. The problem with glomerular regeneration is centered around the podocyte, a highly specialized cell that is the critical constituent of the glomerular filtration barrier.Podocytes are characterized by a complex cytoskeleton that makes them unable to proliferate. Thus, once their depletion reaches a specific threshold, it is considered to be irreversible. The discovery of cells with the aptitude to differentiate into podocytes in the adult kidney, i.e. renal progenitor cells (RPCs), was a critical step in understanding the mechanisms of glomerular repair. Accumulating evidence suggests that a tight regulation of many different signaling pathways, such as Notch, Wnt, and microRNA, is involved in a correct regenerative process and that an altered regulation of these same signaling pathways in RPCs triggers the generation of focal segmental glomerulosclerosis lesions. In particular, regeneration is severely impaired by proteinuria, when albumin sequesters retinoic acid and blocks RPC differentiation in podocytes.RPC maintenance and differentiating potential are regulated by complex mechanisms that can be implemented following glomerular injury and can be manipulated to activate regeneration for therapeutic purposes. A better understanding of the phenomenon of glomerular regeneration paves the way for the prevention and treatment of glomerular diseases.