Focal segmental glomerulosclerosis (FSGS) is a cause of proteinuric kidney disease, compromising both native and transplanted kidneys. Treatment is limited because of a complex pathogenesis, including unknown serum factors. Here we report that serum soluble urokinase receptor (suPAR) is elevated in two-thirds of subjects with primary FSGS, but not in people with other glomerular diseases. We further find that a higher concentration of suPAR before transplantation underlies an increased risk for recurrence of FSGS after transplantation. Using three mouse models, we explore the effects of suPAR on kidney function and morphology. We show that circulating suPAR activates podocyte β3 integrin in both native and grafted kidneys, causing foot process effacement, proteinuria and FSGS-like glomerulopathy. Our findings suggest that the renal disease only develops when suPAR sufficiently activates podocyte β3 integrin. Thus, the disease can be abrogated by lowering serum suPAR concentrations through plasmapheresis, or by interfering with the suPAR–β3 integrin interaction through antibodies and small molecules targeting either uPAR or β3 integrin. Our study identifies serum suPAR as a circulating factor that may cause FSGS.

Many proteins have been proposed to act as surrogate markers of organ damage, yet for many candidates the essential characteristics which link the protein to the injured organ have not yet been described. We generated an NGAL-reporter mouse by inserting a di-fusion reporter gene, Luciferase2(Luc2)/mCherry(mC) into the Ngal locus. The Ngal-Luc2/mC reporter accurately recapitulated the endogenous message and illuminated injuries in vivo in real-time. In the kidney, Ngal-Luc2/mC imaging showed a sensitive, rapid, dose-dependent, reversible, and organ and cellular specific relationship with tubular stress, which quantitatively paralleled urinary Ngal (uNgal). Unexpectedly, specific cells of the distal nephron were the source of uNgal. Cells isolated from Ngal-Luc2/mC mice could also track both the onset and the resolution of the injury, and monitor the actions of NF-κB inhibitors and antibiotics in the case of infection. Accordingly, the imaging of Ngal-Luc2/mC mice and cells identified injurious and reparative agents which effect kidney damage.

α-Intercalated cells (A-ICs) within the collecting duct of the kidney are critical for acid-base homeostasis. Here, we have shown that A-ICs also serve as both sentinels and effectors in the defense against urinary infections. In a murine urinary tract infection model, A-ICs bound uropathogenic E. coli and responded by acidifying the urine and secreting the bacteriostatic protein lipocalin 2 (LCN2; also known as NGAL). A-IC-dependent LCN2 secretion required TLR4, as mice expressing an LPS-insensitive form of TLR4 expressed reduced levels of LCN2. The presence of LCN2 in urine was both necessary and sufficient to control the urinary tract infection through iron sequestration, even in the harsh condition of urine acidification. In mice lacking A-ICs, both urinary LCN2 and urinary acidification were reduced, and consequently bacterial clearance was limited. Together these results indicate that A-ICs, which are known to regulate acid-base metabolism, are also critical for urinary defense against pathogenic bacteria. They respond to both cystitis and pyelonephritis by delivering bacteriostatic chemical agents to the lower urinary system.

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OBJECTIVE-The aim of our study was to explore the immunomodulatory activity of soluble immunoglobulin (Ig)-like transcript (ILT) 3-Fc in pancreatic islet transplantation and to determine its mechanism of action.RESEARCH DESIGN AND METHODS-NOD/SCID mice in which diabetes was induced by streptozotocin injection were transplanted with human pancreatic islet cells. Mice in which the transplant restored euglycemia were humanized with allogeneic peripheral blood mononuclear cells and treated with ILT3-Fc or control human IgG or left untreated. The blood glucose level was monitored twice a week, and rejection was diagnosed after two consecutive readings Ͼ350 mg/dl. Tolerated and rejected grafts were studied histologically and by immunostaining for human T-cells and insulin production. CD4 and CD8 T-cells from the spleen were studied for suppressor activity, expression of cytokines, and CD40L. RESULTS-Although human T-cell engraftment was similar inall groups, ILT3-Fc-treated mice tolerated the islets for the entire period of observation (91 days), whereas control mice rejected the graft within 7 weeks (P Ͻ 0.0001). ILT3-Fc treatment suppressed the expression of cytokines and CD40L and induced the differentiation of human CD8 ϩ T suppressor cells that inhibited Th alloreactivity against graft HLA antigens. T-cells allostimulated in vitro in the presence of ILT3-Fc inhibited CD40L-induced upregulation of CD40 in human pancreatic islet cells. Histochemical studies showed dramatic differences between human pancreatic islets from tolerant, ILT3-Fc-treated mice and control recipients rejecting the grafts.CONCLUSIONS-The data indicated that ILT3-Fc is a potent immunoregulatory agent that suppressed islet allograft rejection in humanized NOD/SCID mice.

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The laser-diffraction method (LDM) can rapidly determine soil particlesize distributions (PsDs), but LDM-derived PsDs cannot be directly used to classify soil textures by referring to the standards of the classical sievepipette method (sPM). Our objectives were to explore calibration models for converting PsD data from LDM (volume, %) to sPM (mass, %), and to evaluate the precision of textural classification by using LDM data. we determined the PsDs using both methods for 235 soil samples of various textures collected from three typical land uses, on the Loess Plateau of China. The LDM generally underestimated clay fractions by an average of 45.1%, and overestimated silt fractions by an average of 18.3% compared with sPM. Differences in PsD data between the two methods, indicated by coefficient Cs, increased with increasing clay contents for the 235 samples (P < 0.05). Three calibration models could, however, convert the clay, silt, and sand contents from the volume percentage (LDM) to the mass percentage (sPM). After the conversion, the mean coefficient C between the two methods decreased from 7.9 to 4.1% for the validation samples (n = 78). The distributions of soil textures within the usDA textural triangle agreed well in 71 of the 78 samples, for measured and converted PsD data. The three types of land use did not affect the differences between measured and converted PsD data (P > 0.05). soil textures can thus be rapidly determined by converting PsD data from the faster volume-based LDM to data equivalent to the mass-based sPM, independent of land-use type.

Tree mortality due to warming and drought is a critical aspect of forest ecosystem in responding to climate change. Spatial patterns of tree mortality induced by drought and its influencing factors, however, have yet to be documented at the global scale. We collected observations from 248 sites globally where trees have died due to drought and then assessed the effects of climatic and forest factors on the rate of tree mortality. The global mean annual mortality rate was 5.5%. The rate of tree mortality was significantly and negatively correlated with mean annual precipitation (P < 0.01). Tree mortality was lowest in tropical rainforests with mean annual precipitation >2000 mm and was severe in regions with mean annual precipitation <1000 mm. Mortality rates varied amongst species. The global annual rate of mortality was much higher for gymnosperms (7.1%) than angiosperms (4.8%) but did not differ significantly between evergreen (6.2%) and deciduous (6.1%) species. Stand age and wood density affected the mortality rate. Saplings (4.6%) had a higher mortality rate than mature trees (3.2%), and mortality rates significantly decreased with increasing wood density for all species (P < 0.01). We therefore concluded that the tree mortality around the globe varied with climatic and forest factors. The differences between tree species, wood density, stand density, and stand age should be considered when evaluating tree mortality at a large spatial scale during future climatic extremes.