Citations

Hepatorenal syndrome (HRS) is a functional form of acute kidney injury (AKI) associated with advanced liver cirrhosis or fulminant hepatic failure. Various new concepts have emerged since the initial diagnostic criteria and definition of HRS was initially published. These include better understanding of the pathophysiological mechanisms involved in HRS, identification of bacterial infection (especially spontaneous bacterial peritonitis) as the most important HRS-precipitating event, recognition that insufficient cardiac output plays a role in the occurrence of HRS, and evidence that renal failure reverses with pharmacotherapy. Patients with HRS are often critically ill and, by definition, have multiorgan failure. The purpose of this review is to provide an update on novel advances in HRS, with emphasis on the different aspects of management of these patients in the intensive care unit.

RanBP2/Nup358, the major component of the cytoplasmic filaments of the nuclear pore complex (NPC), is essential for mouse embryogenesis and is implicated in both macromolecular transport and mitosis, but its specific molecular functions are unknown. Using RanBP2 conditional knockout mouse embryonic fibroblasts and a series of mutant constructs, we show that transport, rather than mitotic, functions of RanBP2 are required for cell viability. Cre-mediated RanBP2 inactivation caused cell death with defects in M9- and classical nuclear localization signal (cNLS)–mediated protein import, nuclear export signal–mediated protein export, and messenger ribonucleic acid export but no apparent mitotic failure. A short N-terminal RanBP2 fragment harboring the NPC-binding domain, three phenylalanine-glycine motifs, and one Ran-binding domain (RBD) corrected all transport defects and restored viability. Mutation of the RBD within this fragment caused lethality and perturbed binding to Ran guanosine triphosphate (GTP)–importin-β, accumulation of importin-β at nuclear pores, and cNLS-mediated protein import. These data suggest that a critical function of RanBP2 is to capture recycling RanGTP–importin-β complexes at cytoplasmic fibrils to allow for adequate cNLS-mediated cargo import.

AbstractChronic neuropathic pain arising from peripheral nerve damage is a severe clinical issue where there is a major unmet medical need. We previously demonstrated that both neurotensin (NT) receptor subtypes 1 (NTS1) and 2 (NTS2) are involved in mediating the naloxone‐insensitive antinociceptive effects of neurotensin in different analgesic tests including hotplate, tail‐flick, and tonic pain. However, the role of these receptors in neuropathic pain management has been poorly investigated. In the present study, we therefore examined whether intrathecal delivery ofNTS1 agonists was effective in reducing neuropathic pain symptoms in rats. Neuropathy was induced by sciatic nerve constriction (CCImodel), and the development of mechanical allodynia and thermal hyperalgesia on the ipsi‐ and contralateral hind paws was examined 3, 7, 14, 21, and 28 days post‐surgery.CCI‐operated rats exhibited significant increases in thermal and mechanical hypersensitivities over a 28‐day testing period. Spinal injection ofNTtoCCIrats alleviated the behavioral responses to radiant heat and mechanical stimuli, with a maximal reversal of 91% of allodynia at 6 μg/kg. Intrathecal administration of theNTS1‐selective agonist,PD149163 (30–90 μg/kg) also produced potent anti‐allodynic and anti‐hyperalgesic effects in nerve‐injured rats. Likewise, heat hyperalgesia and tactile allodynia produced byCCIof the sciatic nerve were fully reversed by theNTS1 agonist,NT69L(5–25 μg/kg). Altogether, these results support the idea that theNTS1 receptor subtype is involved in pain modulation, and the potential use ofNTS1 agonists for the treatment of painful neuropathies.

Abstract RasGRP1, a Ras guanine-nucleotide exchange factor, critically mediates T cell development and function and controls immunodeficiency and autoimmunity. In this study, we describe a unique mechanism of mobilization and activation of RasGRP1 in response to SDF-1, a chemokine that signals via the G protein-coupled receptor CXCR4. Depletion of RasGRP1 impaired SDF-1–stimulated human T cell migration, expression of the activation marker CD69, and activation of the ERK MAPK pathway, indicating that RasGRP1 mediates SDF-1 functions. SDF-1 treatment caused RasGRP1 to localize to the plasma membrane to activate K-Ras and to the Golgi to activate N-Ras. These events were required for cellular migration and for ERK activation that mediates downstream transcriptional events in response to SDF-1. SDF-1–dependent localization of RasGRP1 did not require its diacylglycerol-binding domain, even though diacyglycerol was previously shown to mediate localization of RasGRP1 in response to Ag stimulation. This domain was, however, required for activity of RasGRP1 after its localization. Intriguingly, SDF-1 treatment of T cells induced the formation of a novel molecular signaling complex containing RasGRP1, Gαi2, and ZAP-70. Moreover, SDF-1–mediated signaling by both Gi proteins and ZAP-70 was required for RasGRP1 mobilization. In addition, RasGRP1 mobilization and activation in response to SDF-1 was dependent on TCR expression, suggesting that CXCR4 heterodimerizes with the TCR to couple to ZAP-70 and mobilize RasGRP1. These results increase understanding of the molecular mechanisms that mediate SDF-1 effects on T cells and reveal a novel mechanism of RasGRP1 regulation. Other G protein-coupled receptors may similarly contribute to regulation of RasGRP1.