Showing papers by "Raghu Kalluri published in 2004"

Cancer without disease.

Abstract: Do inhibitors of blood-vessel growth found naturally in our bodies defend most of us against progression of cancer to a lethal stage?

Induction of B7-1 in podocytes is associated with nephrotic syndrome

Abstract: Kidney podocytes and their slit diaphragms form the final barrier to urinary protein loss. This explains why podocyte injury is typically associated with nephrotic syndrome. The present study uncovered an unanticipated novel role for costimulatory molecule B7-1 in podocytes as an inducible modifier of glomerular permselectivity. B7-1 in podocytes was found in genetic, drug-induced, immune-mediated, and bacterial toxin-induced experimental kidney diseases with nephrotic syndrome. The clinical significance of our results is underscored by the observation that podocyte expression of B7-1 correlated with the severity of human lupus nephritis. In vivo, exposure to low-dose LPS rapidly upregulates B7-1 in podocytes of WT and SCID mice, leading to nephrotic-range proteinuria. Mice lacking B7-1 are protected from LPS-induced nephrotic syndrome, suggesting a link between podocyte B7-1 expression and proteinuria. LPS signaling through toll-like receptor-4 reorganized the podocyte actin cytoskeleton in vitro, and activation of B7-1 in cultured podocytes led to reorganization of vital slit diaphragm proteins. In summary, upregulation of B7-1 in podocytes may contribute to the pathogenesis of proteinuria by disrupting the glomerular filter and provides a novel molecular target to tackle proteinuric kidney diseases. Our findings suggest a novel function for B7-1 in danger signaling by nonimmune cells.

The role of epithelial-to-mesenchymal transition in renal fibrosis

Abstract: Epithelial-to-mesenchymal transition (EMT) involving injured epithelial cells plays an important role in the progression of fibrosis in the kidney. Tubular epithelial cells can acquire a mesenchymal phenotype, and enhanced migratory capacity enabling them to transit from the renal tubular microenvironment into the interstitial space and escape potential apoptotic cell death. EMT is a major contributor to the pathogenesis of renal fibrosis, as it leads to a substantial increase in the number of myofibroblasts, leading to tubular atrophy. However, recent findings suggest that EMT involving tubular epithelial cell is a reversible process, potentially determined by the surviving cells to facilitate the repopulation of injured tubules with new functional epithelia. Major regulators of renal epithelial cell plasticity in the kidney are two multifunctional growth factors, bone morphogenic protein-7 (BMP-7) and transforming growth factor β1 (TGF-β1). While TGF-β1 is a well-established inducer of EMT involving renal tubular epithelial cells, BMP-7 reverses EMT by directly counteracting TGF-β-induced Smad-dependent cell signaling in renal tubular epithelial cells. Such antagonism results in the repair of injured kidneys, suggesting that modulation of epithelial cell plasticity has therapeutic advantages.

Thrombospondin-1 associated with tumor microenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression.

Abstract: Low-dose cyclophosphamide (LDC) induces selective apoptosis of endothelial cells within the vascular bed of tumors. Here, we investigated a hypothesis that the effect of LDC is mediated by the pro-apoptotic action of endogenous inhibitors of angiogenesis. Tumors treated with LDC demonstrate similar expression of matrix metalloproteinases and also basement membrane-derived angiogenesis inhibitors when compared with wild-type tumors, whereas the expression of thrombospondin-1 (TSP-1) is significantly elevated in LDC-treated tumors. We used mice with an absence of type XVIII collagen (endostatin) or type IV collagen alpha3 chain (tumstatin) or TSP-1 to assess the contribution of these endogenous inhibitors of angiogenesis on LDC-mediated tumor suppression. Lack of TSP-1 in the host in addition to tumor cells leads to diminished capacity of LDC to suppress tumor growth, whereas the absence of endostatin and tumstatin did not alter the effect of LDC. LDC treatment predominantly induces selective expression of TSP-1 in tumor cells and peri-vascular cells and facilitates apoptosis of proliferating endothelial cells, with minimal direct effect on tumor cells and peri-vascular cells. These studies indicate that TSP-1 contributes to tumor growth suppression induced by LDC and suggest that tumors that express high basal level of TSP-1 may be more susceptible to tumor suppression by such a regimen. This study also makes a strong case for TSP-1 expression levels as a potential predictive marker for the successful use of LDC in cancer patients.

The contribution of vascular basement membranes and extracellular matrix to the mechanics of tumor angiogenesis

Abstract: The goal of this review is to highlight the contribution of extracellular matrix and vascular basement membranes to the regulation of angiogenesis and tumor progression. Here we present a new concept that vascular basement membrane influences endothelial cells and possibly other cell types in a solid state assembled form, and also in a degraded solution state form. Depending on the structural integrity, composition and exposure of cryptic sites, the vascular basement membrane proteome exerts functional influences on proliferating and resting endothelial cells. This review provides the reader with an appreciation of this newly evolved concept in the area of vascular biology.

A domain-specific usherin/collagen IV interaction may be required for stable integration into the basement membrane superstructure.

Abstract: Usherin is a basement membrane protein encoded by the gene associated with Usher syndrome type IIa, the most common deaf/blind disorder. This report demonstrates a specific interaction between type IV collagen and usherin in the basement membrane, with a 1:1 stoichiometry for binding. Genetic and biochemical approaches were used to explore the role of type IV collagen binding in usherin function. We demonstrate binding occurs between the LE domain of usherin and the 7S domain of type IV collagen. A purified fusion peptide comprising the first four LE modules was shown to compete with full-length recombinant usherin for type IV collagen binding. However, synonymous fusion peptides with single amino acid substitutions resulting from missense mutations that were known to cause Usher syndrome type IIa in humans, failed to compete. Only mutations in loop b of the LE domain abolished binding activity. Co-immunoprecipitation and western blot analysis of testicular basement membranes from the Alport mouse model show a 70% reduction in type IV collagen is associated with a similar reduction in usherin, suggesting the usherin/collagen (IV) interaction stabilizes usherin in the basement membrane. Thus, the domain-specific interaction between usherin and type IV collagen appears essential to usherin stability in vivo, and loss of this interaction may result in Usher pathology in humans.

Are there endogenous molecules that protect kidneys from injury? The case for bone morphogenic protein-7 (BMP-7).

Abstract: Injury to the kidney can be initiated via diverse mechanisms, such as genetic defects, autoimmune reactions, environmental insults and metabolic defects [1,2]. Based on the kinetics of disease progression, renal injury is traditionally grouped as either being an acute or chronic effect [3,4]. While the kidney displays an enormous potential to regenerate after acute renal injury, chronic renal disease is generally irreversible [1,5,6]. The switch from the normal potential to repair after acute injury, to an irreversible chronic disease phase, is not yet well understood. It has been suggested that an imbalance of growth factors/hormones that regulate renal cell behaviour might play an important role in determining the pathological fate of the kidney [7,8].

Experimental strategies to reverse chronic renal disease

Abstract: Progression of chronic nephropathies still represents a major challenge for clinical nephrologists. Specific therapies that prevent patients from requiring dialysis or transplantation are still not available. However, recent experimental studies have demonstrated that regression of advanced lesions in the kidney can be achieved. This review summarizes the recent therapeutic advances using experimental models that might translate into novel human therapies to prevent, or significantly delay, requirement of renal replacement therapy.

Allograft rejection and glomerular basement membrane antibodies in Alport's syndrome.

Abstract: Background Anti-glomerular basement membrane (GBM) antibodies occasionally occur in Alport patients after renal allograft transplantation. Methods We report a patient with Alport's syndrome who lost four transplants each within the first year post transplantation. We searched for the presence of anti-GBM antibodies using recombinant NC1 domains of type IV collagen. Immunoblotting, enzyme linked immunosorbent assay (ELISA), and immunofluorescence were used to detect the presence of antibodies against the glomerular basement membrane. Results High antibody titers to the alpha3 chain (the Goodpasture antigen) and alpha5 chain of type IV collagen were detected. Review of pathologic specimens showed features of vascular rejection in all specimens. Conclusion The association of high titer anti-GBM antibodies and vascular rejection may be important. When vascular rejection occurs in Alport patients, the presence of anti-GBM antibodies should be sought. Recombinant anti-GBM assays should be used if standard anti-GBM testing is equivocal.