POEMS syndrome, calciphylaxis and focal segmental glomerulosclerosis - VEGF as a possible link.

BACKGROUND: Polyneuropathy organomegaly endocrinopathy M-protein skin changes (POEMS) syndrome is a rare cause of polyneuropathy. Calciphylaxis, a severe disease leading to necrotic ulcers of the skin, is associated with POEMS syndrome and also with renal disease. This case report describes a patient with POEMS syndrome plus primary focal segmental glomerulosclerosis. CASE PRESENTATION: A 27-year-old Caucasian woman with chronic renal insufficiency due to focal segmental glomerulosclerosis and calciphylaxis presented to our institution with polyneuropathy and encephalopathy. An extensive diagnostic workup revealed POEMS syndrome. Serum concentrations of vascular endothelial growth factor (VEGF) were highly elevated, consistent with POEMS syndrome. CONCLUSION: To our knowledge, this is the first report of a patient with POEMS syndrome and primary focal segmental glomerulosclerosis. The combination of POEMS syndrome, calciphylaxis and primary focal segmental glomerulosclerosis may be coincidental, suggesting the need for additional studies to confirm or exclude this association. VEGF may be an important pathogenetic link, suggesting that treatment with antiangiogenic agents may improve patient outcomes.

Insulin modulates the inflammatory granulocyte response to streptococci via phosphatidylinositol 3-kinase.

Group B streptococci (GBS; Streptococcus agalactiae) are a major cause of invasive infections in newborn infants and in patients with type 2 diabetes. Both patient groups exhibit peripheral insulin resistance and alterations in polymorphonuclear leukocyte (PML) function. In this investigation, we studied the PML response repertoire to GBS with a focus on TLR signaling and the modulation of this response by insulin in mice and humans. We found that GBS-induced, MyD88-dependent chemokine formation of PML was specifically downmodulated by insulin via insulin receptor-mediated induction of PI3K. PI3K inhibited transcription of chemokine genes on the level of NF-κB activation and binding. Insulin specifically modulated the chemokine response of PML to whole bacteria, but affected neither activation by purified TLR agonists nor antimicrobial properties, such as migration, phagocytosis, bacterial killing, and formation of reactive oxygen species. The targeted modulation of bacteria-induced chemokine formation by insulin via PI3K may form a basis for the development of novel targets of adjunctive sepsis therapy.

The nephronophthisis gene product NPHP2/Inversin interacts with Aurora A and interferes with HDAC6-mediated cilia disassembly.

BACKGROUND: Nephronophthisis (NPH) is a rare recessive disease caused by several different gene mutations. Most gene products localize to the cilium, and thus, the various NPH manifestations including kidney cysts and situs inversus have been linked to ciliary defects. RESULTS: Here, we describe that targeted knockdown of NPHP2 significantly reduced the number of cilia on polarized MDCK cells. As one of the underlying molecular mechanisms, we identified a direct interaction between NPHP2 and Aurora A, a cell cycle kinase that promotes ciliary disassembly after activation by Hef1. NPHP2 inhibited the phosphorylation and activation of Aurora A, and reduced its kinase activity in vitro. Aurora A and histone deacetylase inhibitors ameliorated the ciliogenesis defect in NPHP2-deficient MDCK cells, supporting our hypothesis that NPHP2 is involved in the control of ciliary disassembly. Furthermore, we observed that nephrocystin (NPHP1), an interaction partner of NPHP2, also binds Aurora A, exerting very similar inhibitory effects on Hef1-mediated Aurora A activation. CONCLUSIONS: Taken together, these findings suggest that NPHP gene products can interfere with ciliary disassembly through interaction with the Hef1/Aurora A module, thereby modulating cell cycle control and cell proliferation.

A Cilia Independent Role of Ift88/Polaris during Cell Migration.

Ift88 is a central component of the intraflagellar transport (Ift) complex B, essential for the building of cilia and flagella from single cell organisms to mammals. Loss of Ift88 results in the absence of cilia and causes left-right asymmetry defects, disordered Hedgehog signaling, and polycystic kidney disease, all of which are explained by aberrant ciliary function. In addition, a number of extraciliary functions of Ift88 have been described that affect the cell-cycle, mitosis, and targeting of the T-cell receptor to the immunological synapse. Similarly, another essential ciliary molecule, the kinesin-2 subunit Kif3a, which transports Ift-B in the cilium, affects microtubule (MT) dynamics at the leading edge of migrating cells independently of cilia. We now show that loss of Ift88 impairs cell migration irrespective of cilia. Ift88 is required for the polarization of migrating MDCK cells, and Ift88 depleted cells have fewer MTs at the leading edge. Neither MT dynamics nor MT nucleation are dependent on Ift88. Our findings dissociate the function of Ift88 from Kif3a outside the cilium and suggest a novel extraciliary function for Ift88. Future studies need to address what unifying mechanism underlies the different extraciliary functions of Ift88.

ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3.

Nephronophthisis is an autosomal recessive cystic kidney disease that leads to renal failure in childhood or adolescence. Most NPHP gene products form molecular networks. Here we identify ANKS6 as a new NPHP family member that connects NEK8 (NPHP9) to INVS (NPHP2) and NPHP3. We show that ANKS6 localizes to the proximal cilium and confirm its role in renal development through knockdown experiments in zebrafish and Xenopus laevis. We also identify six families with ANKS6 mutations affected by nephronophthisis, including severe cardiovascular abnormalities, liver fibrosis and situs inversus. The oxygen sensor HIF1AN hydroxylates ANKS6 and INVS and alters the composition of the ANKS6-INVS-NPHP3 module. Knockdown of Hif1an in Xenopus results in a phenotype that resembles loss of other NPHP proteins. Network analyses uncovered additional putative NPHP proteins and placed ANKS6 at the center of this NPHP module, explaining the overlapping disease manifestation caused by mutation in ANKS6, NEK8, INVS or NPHP3.