A number of genes involved in kidney development are reactivated in

A number of genes involved in kidney development are reactivated in the adult after acute kidney injury (AKI). to an embryonic state. We will show that reactivation of these developmental genes is often associated with expression in cells that are not normally involved in mediating parallel responses in the embryo and that depending on the cellular context these responses can have beneficial or detrimental effects on injury and repair after AKI. and KPT185 in orthotopic transplant models45 46 However regenerating tubular cells express mRNAs after IR-AKI in mice40 and CD24 positive cells have also been shown to express Kim1 in human kidneys47. This has led to the alternate hypothesis that CD24 and CD133 expression reflects de-differentiation of injured cells rather than a stem cell KPT185 state44 48 49 Having said that KPT185 long-term lineage pulse-chase experiments indicate that tubular cells have a remarkable regenerative capacity after IR-AKI43. This raises the possibility that expression of these markers reflects an acquired phenotypic change from an adult terminally differentiated epithelium to a progenitor-like state with greater proliferative capacity more closely resembling the embryonic kidney epithelium. Endothelium Endothelial injury increases the extent of injury after IR-AKI by further decreasing capillary blood flow and increasing inflammatory cell recruitment23. Importantly there is increasing evidence that peri-tubular capillary rarefaction which occurs after IR-AKI50 51 promotes long-term tissue hypoxia which impairs tubular repair and resolution of fibrosis52. The mechanism of microvascular rarefaction is unclear since there is little evidence of endothelial cell death or proliferative repair after AKI51 53 However bi-directional signaling between vascular pericytes and endothelium regulates vascular stability suggesting that capillary rarefaction might result from KPT185 loss of normal pericytes-endothelial interactions after AKI54. Support for this hypothesis comes from a series of studies demonstrating that interference with pericytes-derived signals that stabilize (TIMP3 and EphrinB2) or destabilize (VEGF and ADAMTS1) the microvasculature exacerbates KPT185 or attenuates respectively renal fibrosis after AKI55-57. Fibroblasts and pericytes Wound healing studies indicate that expansion of collagen producing myofibroblasts plays an important role in tissue remodeling including epithelial repair and vascularization58. However persistent expansion of myofibroblasts is associated with fibrosis. In the kidney it is likely that myofibroblasts are derived from different cell types59. However fate mapping using FOXD1 Cre mice to label stromal lineages during embryonic kidney development indicates that the bulk of these cells originate from vascular pericytes that have delaminated from the vessel wall post-AKI29. Thus expansion of myofibroblasts is intimately linked with microvascular de-stabilization. Moreover close proximity between tubular epithelium interstitial inflammatory cells and myofibroblasts provides the FLJ22263 ideal microenvironment for cross talk between these cell types during tissue repair. Macrophages Endothelial and tubular injury promotes recruitment of neutrophils macrophages and lymphocytes in the kidney after AKI60 61 These events amplify the inflammatory response extending tissue injury and facilitating phagocytosis of dying cells. However paracrine signaling from renal macrophages also plays an important role in promoting tubular repair and interstitial remodeling at later time points after AKI25 62 Signals promoting phenotypic switching from KPT185 pro-inflammatory to regenerative macrophages include active phagocytosis of dying cells (including infiltrating neutrophils)25 as well as the secretion of macrophage growth factors CSF-1 and CSF-2 by tubular epithelial cells63 64 Using knowledge of embryonic kidney development to understand cellular repair after AKI The coordinated mechanisms of repair involving both cell autonomous (intrinsic) and paracrine interactions between epithelium endothelium pericytes and macrophages after AKI is reminiscent of the cellular.