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. Author manuscript; available in PMC: 2026 Jun 15.
Published in final edited form as: Nat Rev Drug Discov. 2025 Mar 18;24(7):543–569. doi: 10.1038/s41573-025-01158-9

Fig. 5 |. Key pathways of chronic kidney disease and fibrosis.

Fig. 5 |

a, Tubule epithelial injury is a conserved mechanism across most kidney diseases and can occur as a result of hypoxic injury (for example, in acute kidney injury) or glomerular disease with subsequent proteinuria or owing to toxic injury (for example, due to drugs). b, Injured tubule epithelial cells dedifferentiate and drive activation of fibroblasts and pericytes, which detach from capillaries, driving capillary dysfunction, loss and immune cell extravasation. Signalling from epithelial cells and degranulated platelets from microthrombi within the dysfunctional capillaries drives monocyte to SPP1+ macrophage polarization. SPP1+ macrophages (also termed scar-associated macrophages) interact with fibroblasts and pericytes and trigger their myofibroblast differentiation with subsequent extracellular matrix deposition and fibrosis.