Figure 8.

CXC chemokine ligand 12 (CXCL12)–driven podocyte-progenitor feedback mechanism for regenerating injury in cortical glomeruli. (a) Note that focal podocyte injury does not necessarily abrogate the exposure of progenitors within the parietal epithelial cell (PEC) layer to CXCL12 secreted by other podocytes, a process that sustains the inhibition of Notch signaling and progenitor activation that would be needed for podocyte regeneration. CXCL12 blockade can overcome this intrinsic negative feedback and enforce podocyte regeneration, repair glomerular filtration barrier injury, reduce proteinuria, and prevent from glomerulosclerosis. (b) Toxic glomerular injury (red glomeruli) affects predominately glomeruli of juxtamedullary nephrons (large circles) that are also less endowed with podocyte progenitors and therefore frequently end in irreversible glomerular scarring and persistent proteinuria. In contrast, glomeruli of cortical nephrons (smaller circles), that is, 80% of all nephrons, face rather mild podocyte injury (yellow glomeruli) and are equipped with more podocyte progenitors and thus frequently completely recover from filtration barrier injury by podocyte regeneration (green glomeruli); therapeutic CXCL12 inhibition can stimulate progenitor-driven podocyte regeneration according to the predominant distribution of progenitors in cortical nephrons, which improves renal function and reduces proteinuria, with remaining proteinuria from nonregenerated juxtamedullary nephrons.