Volume 93, Issue 1, Pages 27-40 (January 2018) Cellular and molecular pathways of renal repair after acute kidney injury  Sanjeev Kumar  Kidney International  Volume 93, Issue 1, Pages 27-40 (January 2018) DOI: 10.1016/j.kint.2017.07.030 Copyright © 2017 International Society of Nephrology Terms and Conditions

Figure 1 Schematic illustration highlighting patchy regenerative/reparative processes after mammalian acute kidney injury. (Upper panels) Regions of mild to moderate acute nephron injury: the injured nephron epithelia regenerate, and such regions of full repair are restored to their previous morphology. (Lower panels) Nephrons with severe injury leading to extensive epithelial cell loss are less likely to regenerate the injured epithelia in its entirety. Such areas tend to be associated with peritubular capillary dropout with disruption of endothelial cell–pericyte organization, immune/inflammatory cell infiltration, fibroblasts, and α-SMA+ myofibroblasts, thereby highlighting foci of impaired and dysregulated repair processes with aberrant extracellular matrix remodeling. Such microdomains serve as a nidus of fibrosis. α-SMA, α-smooth muscle actin; IRI, ischemia reperfusion injury. Kidney International 2018 93, 27-40DOI: (10.1016/j.kint.2017.07.030) Copyright © 2017 International Society of Nephrology Terms and Conditions

Figure 2 Proximal tubular epithelial cell (PTEC) fate after acute kidney injury. After acute kidney injury, a subset of PTECs undergo necrotic and apoptotic cell death. (a) Early injury/repair response: epithelial injury induces Sox9 (Sox9+Kim1+ PTEC subtype) that regenerates the injured epithelium.29 (b) Chronic injury/repair response (28 days after mice ischemia reperfusion injury): Epithelial cells on successful regeneration shut down Sox9; however, the region of unresolved injury delineated by PTECs that express Kim1 continues to mount an SOX9 response in an attempt to regenerate itself. The majority of the proliferating Ki67+ PTECs at this stage are Sox9+; therefore, in the chronic phase, Sox9+Kim1+ cells demarcate “unresolved injury/repair” PTEC subtype.29 (c) Injury-induced activation of Snai1 and Twist1 confers a partial epithelial to mesenchymal state.38,39 A partial epithelial-mesenchymal transition (EMT) state is associated with acquisition of a pathologic proinflammatory and profibrotic secretome. A subset of such cells has been suggested to be cell-cycle arrested. (d) In the setting of severe acute kidney injury mice models (unilateral ischemia reperfusion injury, severe bilateral ischemia reperfusion injury, and unilateral ureteral obstructive model) and predominant fibrotic models (aristolochic acid nephropathy), G2/M cell cycle–arrested epithelial cells contribute to fibrosis.45 Kim1, kidney injury molecule-1. Kidney International 2018 93, 27-40DOI: (10.1016/j.kint.2017.07.030) Copyright © 2017 International Society of Nephrology Terms and Conditions

Figure 3 Cellular and molecular signaling networks of renal repair. EGFR and STAT3/Birc5 signaling is activated in the TECs after acute kidney injury. Hbegf, a ligand for EGFR signaling released by epithelial cells, activates the EGFR signaling in an autocrine/juxtacrine manner. Csf-1 signaling is activated in epithelial cells, with contribution from the macrophages via paracrine effects and, in turn, promoting M2 macrophage phenotype markers. Macrophage-paracrine effects also activate RA signaling and canonical Wnt/β-catenin signaling within the TECs. IL-22 and MMPs from macrophages and endothelial cells, respectively, have also been suggested to promote renal repair via acting on the TECs. Endothelial cells contribute to repair responses by regulating chronic inflammatory responses via S1pr1 and Hif1α/Hif2α signaling. In addition, endothelial-pericyte intimacy and angiocrine factors such as Vegf, Ang1, and Sirt1 influence renal repair responses. Ang1, angiopoietin-1; Survivin (Birc5)/signal transducer and activator of transcription 3 (STAT3); Csf, colony-stimulating factor; EGFR, epidermal growth factor receptor; Hbegf, heparin binding epidermal growth factor; Hif, hypoxia-inducible factor; IL, interleukin; IRAK-M, interleukin-1 receptor-associated kinase–monocyte/macrophage; MMPs, matrix metalloproteinases; PTECs, proximal tubular epithelial cells; RA, retinoic acid; S1pr1, sphingosine 1-phosphate receptor 1; Sirt, sirtuin 1; TECs, tubular epithelial cells; Vegf, vascular endothelial growth factor. Kidney International 2018 93, 27-40DOI: (10.1016/j.kint.2017.07.030) Copyright © 2017 International Society of Nephrology Terms and Conditions