The Hedgehog (Hh) signaling pathway regulates tissue patterning during development, including patterning and growth of limbs and face, but whether Hh signaling plays a role in adult kidney remains undefined. In this study, using a panel of hedgehog-reporter mice, we show that the two Hh ligands (Indian hedgehog and sonic hedgehog ligands) are expressed in tubular epithelial cells. We report that the Hh effectors (Gli1 and Gli2) are expressed exclusively in adjacent platelet-derived growth factor receptor-β-positive interstitial pericytes and perivascular fibroblasts, suggesting a paracrine signaling loop. In two models of renal fibrosis, Indian Hh ligand was upregulated with a dramatic activation of downstream Gli effector expression. Hh-responsive Gli1-positive interstitial cells underwent 11-fold proliferative expansion during fibrosis, and both Gli1- and Gli2-positive cells differentiated into α-smooth muscle actin-positive myofibroblasts. In the pericyte-like cell line 10T1/2, hedgehog ligand triggered cell proliferation, suggesting a possible role for this pathway in the regulation of cell cycle progression of myofibroblast progenitors during the development of renal fibrosis. The hedgehog antagonist IPI-926 abolished Gli1 induction in vivo but did not decrease kidney fibrosis. However, the transcriptional induction of Gli2 was unaffected by IPI-926, suggesting the existence of smoothened-independent Gli activation in this model. This study is the first detailed description of paracrine hedgehog signaling in adult kidney, which indicates a possible role for hedgehog-Gli signaling in fibrotic chronic kidney disease.

Retinoic acid (RA) has been used therapeutically to reduce injury and fibrosis in models of AKI, but little is known about the regulation of this pathway and what role it has in regulating injury and repair after AKI. In these studies, we show that RA signaling is activated in mouse and zebrafish models of AKI, and that these responses limit the extent of injury and promote normal repair. These effects were mediated through a novel mechanism by which RA signaling coordinated the dynamic equilibrium of inflammatory M1 spectrum versus alternatively activated M2 spectrum macrophages. Our data suggest that locally synthesized RA represses proinflammatory macrophages, thereby reducing macrophage-dependent injury post-AKI, and activates RA signaling in injured tubular epithelium, which in turn promotes alternatively activated M2 spectrum macrophages. Because RA signaling has an essential role in kidney development but is repressed in the adult, these findings provide evidence of an embryonic signaling pathway that is reactivated after AKI and involved in reducing injury and enhancing repair.

These findings indicate that regorafenib induces a coordinated and reversible suppression of NO and stimulation of ET-1. Whether NO and ET-1 might predict therapeutic efficacy in these patients requires further study.

Space travel has grown during the past 2 decades, and is expected to surge in the future with the establishment of an American Space Force, businesses specializing in commercial space travel, and National Aeronautics and Space Administration’s planned sustained presence on the moon. Accompanying this rise, treating physicians are bracing for a concomitant increase in space-related medical problems, including back pain. Back pain is highly prevalent in astronauts and space travelers, with most cases being transient and self-limiting (space adaptation back pain). Pathophysiologic changes that affect the spine occur during space travel and may be attributed to microgravity, rapid acceleration and deceleration, and increased radiation. These include a loss of spinal curvature, spinal muscle atrophy, a higher rate of disc herniation, decreased proteoglycan and collagen content in intervertebral discs, and a reduction in bone density that may predispose people to vertebral endplate fractures. In this article, the authors discuss epidemiology, pathophysiology, prevention, treatment, and future research.