ADAM (a disintegrin and metalloprotease) family proteins play important roles in animal development and pathogenesis. In C. elegans, a secreted ADAM protein, MIG-17, acts from outside the gonad to control the migration of gonadal distal tip cells (DTCs) that promote gonad morphogenesis. Here, we report that dominant mutations in the fbl-1 gene encoding fibulin-1 spliced isoforms, which are calcium binding extracellular matrix proteins, bypass the requirement for MIG-17 activity in directing DTC migration. Specific amino acid substitutions in the third EGF-like motif of one of the two isoforms, FBL-1C, which corresponds to mammalian fibulin-1C, suppress mig-17 mutations. FBL-1C is synthesized in the gut cells and localizes strongly to the gonadal basement membrane in a MIG-17-dependent manner. Localization of mutant FBL-1C is weaker than that of the wild-type protein and is insensitive to MIG-17 activity, suggesting that it gains a novel function that compensates for its reduced molecular density. We propose that proteolysis by MIG-17 recruits FBL-1C to the gonadal basement membrane, where it is required for the guidance of DTCs, and that mutant FBL-1C acts in a manner that mimics the downstream events of MIG-17-mediated proteolysis.

Abstract-Increased renal restive index (RI) measured using Doppler ultrasonography has been shown to correlate with the degree of renal impairment in hypertensive patients. We investigated the prognostic role of RI in cardiovascular and renal outcomes. A total of 426 essential hypertensive subjects (mean age, 63 years; 50% female) with no previous cardiovascular disease were included in this study. Renal segmental arterial RI was measured by duplex Doppler ultrasonography. During follow-up (mean, 3.1 years), 57 participants developed the primary composite end points including cardiovascular and renal outcomes. In multivariate Cox regression analysis, RI was an independent predictor of worse outcome in total subjects (hazard ratio, 1.71 for 1 SD increase), as well as in patients with estimated glomerular filtration rate (eGFR) Ͻ60 mL/min per 1.73 m 2 (hazard ratio, 2.11 for 1 SD increase; PϽ0.01, respectively). When divided into 4 groups based on the respective sex-specific median levels of RI in the eGFR Ն60 and eGFR Ͻ60 mL/min per 1.73 m 2 groups, the group with eGFR Ͻ60 and high RI (male Ն0.73, female Ն0.72) had a significantly poorer event-free survival rate ( 2 ϭ126.4; PϽ0.01), and the adjusted hazard ratio by multivariate Cox regression analysis was 9.58 (95% CI, PϽ0.01). In conclusion, impairment of renal hemodynamics evaluated by increased RI is associated with an increased risk of primary composite end points, and the combination of high RI and low eGFR is a powerful predictor of these diseases in essential hypertension. In hypertensive patients with chronic kidney disease, RI evaluation may complement predictors of cardiovascular and renal outcomes. Key Words: cardiovascular disease Ⅲ renal hemodynamics Ⅲ ultrasonography Ⅲ hypertension Ⅲ predictor I n the past few years, there has been growing attention to markers of subclinical renal damage because they provide an accurate prediction of global cardiovascular outcome.1 Renal Doppler sonography permits noninvasive assessment of intrarenal hemodynamics in addition to evaluation of anatomic information. Intrarenal arterial waveforms recorded by Doppler sonography have been widely used to evaluate renal dysfunction.2,3 Previous studies have explored the capacity of resistive index (RI) calculated from blood flow velocity in vessels to predict the progression of renal function in patients with hypertension, 4 diabetes mellitus, 5 or chronic nephropathy. 6,7 In addition, histological studies demonstrated that RI not only reflects changes in intrarenal perfusion and renovascular resistance but was increased in several pathological conditions, such as renal atherosclerosis 8 and tubulointerstitial damage. 9,10 In previous studies, the prognostic value of RI was examined only in chronic nephropathy, 6 elderly, 11 or heart failure patients 12; however, the results obtained were inconsistent. Thus, the status of RI as an independent cardiovascular risk marker remains to be elucidated. Estimated glomerular filtration rate (eGFR), which is a measure of the kidneys' ...

SummarySalmonella pathogenicity island 1 (SPI1) enables infecting Salmonella to cross the small intestinal barrier and to escape phagocytosis by inducing apoptosis. Several environmental signals and transcriptional regulators modulate the expression of hilA , which encodes a protein playing a central role in the regulatory hierarchy of SPI1 gene expression. We have previously shown that Lon, a stress-induced ATPdependent protease, is a negative regulator of hilA , suggesting that it targets factors required for activating hilA expression. To elucidate the mechanisms by which Lon protease negatively regulates SPI1 transcription, we looked for its substrate proteins. We found that HilC and HilD, which are positive regulators of hilA expression, accumulate in Lon-depleted cells, and that the enhancement of SPI1 expression that occurs in a lon -disrupted mutant is not observed in the lon hilC hilD triple null mutant. Furthermore, we demonstrated that the half-lives of HilC and HilD are, respectively, about 12 times and three times longer in the Lon-depleted mutant, than in the Lon + cells, suggesting that Lon targets both of HilC and HilD. In view of these findings, we suggest that the regulation of SPI1 expression is negatively controlled through degradation of the HilC and HilD transcriptional regulators by Lon.

Mutations in the a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) family of secreted proteases cause diseases linked to ECM abnormalities. However, the mechanisms by which these enzymes modulate the ECM during development are mostly unexplored. The Caenorhabditis elegans MIG-17/AD-AMTS protein is secreted from body wall muscle cells and localizes to the basement membrane (BM) of the developing gonad where it controls directional migration of gonadal leader cells. Here we show that specific amino acid changes in the ECM proteins fibulin-1C (FBL-1C) and type IV collagen (LET-2) result in bypass of the requirement for MIG-17 activity in gonadal leader cell migration in a nidogen (NID-1)-dependent and -independent manner, respectively. The MIG-17, FBL-1C and LET-2 activities are required for proper accumulation of NID-1 at the gonadal BM. However, mutant FBL-1C or LET-2 in the absence of MIG-17 promotes NID-1 localization. Furthermore, overexpression of NID-1 in mig-17 mutants substantially rescues leader cell migration defects. These results suggest that functional interactions among BM molecules are important for MIG-17 control of gonadal leader cell migration. We propose that FBL-1C and LET-2 act downstream of MIG-17-dependent proteolysis to recruit NID-1 and that LET-2 also activates a NID-1-independent pathway, thereby inducing the remodeling of the BM required for directional control of leader cell migration.ECM ͉ fibulin-1 ͉ organogenesis ͉ type IV collagen T he interaction between basement membranes (BMs) and migrating cells or the epithelial layer is a complicated but carefully controlled process that involves remodeling of the ECM. For example, the migration of border cells required for oogenesis and patterning of the early embryo in Drosophila melanogaster is accompanied by precise regulation of the synthesis and degradation of type IV collagen, laminin, and perlecan (1, 2). Fibronectin expression is required for branching morphogenesis of the submandibular salivary gland, lung, and kidney in mouse (3). However, the mechanisms of cell-ECM interactions and the roles of BMs in cell migration remain largely unknown.Gonadogenesis in the nematode Caenorhabditis elegans serves as a simple model system for elucidating the function of BMs in organ morphogenesis. The development of hermaphrodite gonads is regulated by the migration of gonadal distal tip cells (DTCs), which promote directional elongation of the gonad arms during the larval stages to form the U-shaped gonads found in adult animals (4, 5). Two secreted a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) family metalloproteases, MIG-17 and GON-1, are involved in this process. GON-1 is required for DTC motility, whereas MIG-17 controls the direction of DTC movement but does not control DTC motility per se (6, 7). MIG-17 is expressed in the body wall muscles and is localized to the BM of the gonad surface, where it is required for DTC migration (7,8). It has been proposed that MIG-17 and GON-1 remodel BMs via prote...

These results suggest that increased RI may be a marker of subclinical TOD in patients with essential hypertension.