Periostin Promotes Cell Proliferation and Macrophage Polarization to Drive Repair after AKI

Significance Statement Studies in animal models and human biopsy specimens have associated the matricellular protein periostin with CKD progression, but its role in AKI is unknown. To investigate periostin’s role in AKI in an ischemia-reperfusion injury model, they used mice with tubule-specific overexpression of periostin and mice lacking periostin expression. They also conducted in vitro studies in primary cultures of isolated tubular cells subjected to hypoxia reoxygenation. Periostin produced by damaged epithelial cells after acute ischemic injury protected epithelial cells from persistent cell cycle arrest and death and promoted a proregenerative macrophage phenotype, both of which contribute to more efficient repair of the injured epithelium. The study’s findings implicate periostin as a novel mediator of renal repair after AKI, and may provide insights into repair mechanisms after AKI. Background The matricellular protein periostin has been associated with CKD progression in animal models and human biopsy specimens. Periostin functions by interacting with extracellular matrix components to drive collagen fibrillogenesis and remodeling or by signaling through cell-surface integrin receptors to promote cell adhesion, migration, and proliferation. However, its role in AKI is unknown. Methods We used mice with conditional tubule-specific overexpression of periostin or knockout mice lacking periostin expression in the renal ischemia-reperfusion injury model, and primary cultures of isolated tubular cells in a hypoxia-reoxygenation model. Results Tubular epithelial cells showed strong production of periostin during the repair phase of ischemia reperfusion. Periostin overexpression protected mice from renal injury compared with controls, whereas knockout mice showed increased tubular injury and deteriorated renal function. Periostin interacted with its receptor, integrin- β 1, to inhibit tubular cell cycle arrest and apoptosis in in vivo and in vitro models. After ischemia-reperfusion injury, periostin-overexpressing mice exhibited diminished expression of proinflammatory molecules and had more F4/80 + macrophages compared with knockout mice. Macrophages from periostin-overexpressing mice showed increased proliferation and expression of proregenerative factors after ischemia-reperfusion injury, whereas knockout mice exhibited the opposite. Coculturing a macrophage cell line with hypoxia-treated primary tubules overexpressing periostin, or treating such macrophages with recombinant periostin, directly induced macrophage proliferation and expression of proregenerative molecules. Conclusions In contrast to the detrimental role of periostin in CKD, we discovered a protective role of periostin in AKI. Our findings suggest periostin may be a novel and important mediator of mechanisms controlling renal repair after AKI.