The matricellular functions of small leucine-rich proteoglycans (SLRPs)

The small leucine-rich proteoglycans (SLRPs) are biologically active components of the extracellular matrix (ECM), consisting of a protein core with leucine rich-repeat (LRR) motifs covalently linked to glycosaminoglycan (GAG) side chains. The diversity in composition resulting from the various combinations of protein cores substituted with one or more GAG chains along with their pericellular localization enables SLRPs to interact with a host of different cell surface receptors, cytokines, growth factors, and other ECM components, leading to modulation of cellular functions. SLRPs are capable of binding to: (i) different types of collagens, thereby regulating fibril assembly, organization, and degradation; (ii) Toll-like receptors (TLRs), complement C1q, and tumor necrosis factor-alpha (TNFα), regulating innate immunity and inflammation; (iii) epidermal growth factor receptor (EGF-R), insulin-like growth factor receptor (IGF-IR), and c-Met, influencing cellular proliferation, survival, adhesion, migration, tumor growth and metastasis as well as synthesis of other ECM components; (iv) low-density lipoprotein receptor-related protein (LRP-1) and TGF-β, modulating cytokine activity and fibrogenesis; and (v) growth factors such as bone morphogenic protein (BMP-4) and Wnt-I-induced secreted protein-1 (WISP-1), controlling cell proliferation and differentiation. Thus, the ability of SLRPs, as ECM components, to directly or indirectly regulate cell-matrix crosstalk, resulting in the modulation of various biological processes, aptly qualifies these compounds as matricellular proteins

Alterations of cathepsins B, H and L in proximal tubules from polycystic kidneys of the Han:SPRD rat

Alterations of cathepsins B, H and L in proximal tubules from polycystic kidneys of the Han:SPRD rat. Abnormalities of tubular matrix metalloproteinases have been shown recently to occur early in the course of polycystic kidney disease (PKD). The present study was conducted to determine whether lysosomal cysteine proteinases were altered in proximal tubules from 2-month-old, heterozygous Han:SPRD rats. The activities of cathepsins B (-45%), H (-39%) and L (-37%) were significantly lower in proximal tubules from PKD rats as compared to healthy offspring. Enzyme proteins were also decreased (cath. B, 2.4 ± 0.7-fold; cath. H, 1.9 ± 0.6-fold; N = 4, P < 0.05), while mRNA levels for cathepsins B, H and L were not different. Tubular cystatin C, a major inhibitor of cathepsins, was normal with regard to protein and mRNA levels in PKD animals. The decrease in cathepsins in PKD was specific for tubules, as enzyme activities in glomeruli and liver tissue were unchanged and limited to the lysosomal compartment, since marker enzymes for cytoplasm, endoplasmatic reticulum and mitochondria were all normal. Intralysosomally, soluble enzymes like cathepsins and β-NAG were decreased, while membrane-bound acid phosphatase was unchanged. The presence of cathepsins could be demonstrated in cyst fluid from homozygous PKD rats and urinary excretion of cathepsins was enhanced in heterozygous animals. Taken together, these findings indicate that the reduction in tubular cathepsins B, H and L was neither due to decreased gene expression nor to upregulation of specific inhibitors, but was likely due to enhanced apical secretion of these enzymes

Quark condensate in one-flavor QCD

We compute the condensate in QCD with a single quark flavor using numerical simulations with the overlap formulation of lattice fermions. The condensate is extracted by fitting the distribution of low lying eigenvalues of the Dirac operator in sectors of fixed topological charge to the predictions of Random Matrix Theory. Our results are in excellent agreement with estimates from the orientifold large-N_c expansion.Comment: 12 pages, 4 figures, REVTeX4, v2: Small changes, extended introduction, published versio

Tubular gelatinase A (MMP-2) and its tissue inhibitors in polycystic kidney disease in the Han:SPRD rat

Tubular gelatinase A (MMP-2) and its tissue inhibitors in polycystic kidney disease in the Han:SPRD rat. Thickening of the tubular basement membrane is one of the hallmarks of polycystic kidney disease (PKD). The present study was conducted to investigate the potential role of the matrix metalloproteinase-2 (MMP-2) and its specific tissue inhibitors (TIMP-1 and TIMP-2) in the accumulation of matrix components in PKD. As a model of PKD, two-month-old heterozygous Han:SPRD rats, which are at an early stage of cystogenesis, were used. MMP-2, but not MMP-9 (gelatinase B) nor MMP-3 (stromelysin) could be detected in proximal tubules of the normal rat kidney. The presence of the inhibitors TIMP-1 and TIMP-2 was confirmed on the mRNA level. In tubules from PKD rats MMP-2 activity was lower (31 ± 8 vs. 58 ± 7 U/prep., N = 9, P < 0.05), mRNA of MMP-2 was reduced 4.2 ± 0.6-fold (N = 4, P < 0.05) and enzyme protein was depressed 3.8 ± 0.8-fold (N = 4, P < 0.05). By contrast, TIMP-1 mRNA was 9.0 ± 1.1-fold and TIMP-2 mRNA 3.8 ± 0.7-fold (N = 4, P < 0.05) elevated over controls. Cyst fluid from homozygous rats contained MMP-2 protein and activity. These findings indicate that tubular MMP-2 activity is reduced in PKD, due to down-regulation of MMP-2, up-regulation of TIMP-1 and TIMP-2, and luminal secretion of the enzyme. It is conceivable that these alterations relate to the enhanced matrix accumulation observed in the evolution of PKD

Small proteoglycans of normal adult human kidney: Distinct expression patterns of decorin, biglycan, fibromodulin, and lumican

Small proteoglycans of normal adult human kidney: Distinct expression patterns of decorin, biglycan, fibromodulin, and lumican.BackgroundAmong the members of the small leucine-rich proteoglycan family, decorin, biglycan, and fibromodulin have been proposed to be potent modulators of transforming growth factor-β (TGF-β) activity, thereby playing an important role in the pathogenesis of fibrotic kidney diseases. Furthermore, decorin expression influences the expression of p21WAF1/CIP1, which has been related to kidney hypertrophy and hyperplasia. However, none of the members of this proteoglycan family have been investigated in normal adult human kidney cortex, thus making it impossible to correlate disease-mediated alterations of their expression with the normal situation in vivo.MethodsThe chondroitin/dermatan sulfate proteoglycans, decorin and biglycan, and the keratan sulfate proteoglycans, fibromodulin and lumican, were investigated in normal human adult renal cortex by immunohistochemistry on the light and electron microscopic level and by in situ hybridization. Northern blot and reverse transcription-polymerase chain reaction (RT-PCR) methods were used to get an estimate of their expression in isolated glomeruli. Decorin excretion with the urine was measured by Western blotting.ResultsTwo bands of decorin and a single band of biglycan mRNA were identified in Northern blots of isolated glomeruli. Amplification by RT-PCR was required to detect the signals for fibromodulin and lumican. All four proteoglycans were preferentially expressed in the renal interstitium with accumulations around tubules. Weak expression was found in the mesangial matrix. Biglycan was expressed by glomerular endothelial cells and, together with fibromodulin, was synthesized and deposited in distal tubular cells and collecting ducts. Immunogold labeling indicated the presence of the proteoglycans in the glomerular basement membrane, which was interpreted as a result of glomerular filtration. Indirect evidence suggested tubular reuptake of decorin after glomerular filtration.ConclusionThe data indicate that the different cells of the adult human kidney are characterized by a distinct expression pattern of the four small proteoglycans. It is suggested that these proteoglycans may have distinct pathophysiological roles depending upon whether they are expressed by mesangial cells, endothelial cells, epithelial cells, or cells of the tubulointerstitium

Setting the scale for the Luescher-Weisz action

We study the quark-antiquark potential of quenched SU(3) lattice gauge theory with the Luescher-Weisz action. After blocking the gauge fields with the recently proposed hypercubic transformation we compute the Sommer parameter, extract the lattice spacing a and set the scale at 6 different values of the gauge coupling in a range from a = 0.084 fm to 0.136 fm.Comment: Remarks and references added, to appear in Phys. Rev.

Global analysis of depletion and recovery of seabed biota after bottom trawling disturbance

Bottom trawling is the most widespread human activity affecting seabed habitats. Here, we collate all available data for experimental and comparative studies of trawling impacts on whole communities of seabed macroinvertebrates on sedimentary habitats and develop widely applicable methods to estimate depletion and recovery rates of biota after trawling. Depletion of biota and trawl penetration into the seabed are highly correlated. Otter trawls caused the least depletion, removing 6% of biota per pass and penetrating the seabed on average down to 2.4 cm, whereas hydraulic dredges caused the most depletion, removing 41% of biota and penetrating the seabed on average 16.1 cm. Median recovery times posttrawling (from 50 to 95% of unimpacted biomass) ranged between 1.9 and 6.4 y. By accounting for the effects of penetration depth, environmental variation, and uncertainty, the models explained much of the variability of depletion and recovery estimates from single studies. Coupled with large-scale, high-resolution maps of trawling frequency and habitat, our estimates of depletion and recovery rates enable the assessment of trawling impacts on unprecedented spatial scales