Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glomerular mesangial cells both synthesize and respond to insulin-like growth factor-1 (IGF-1). Increased activity of the IGF signaling pathway has been implicated as a major contributor to renal enlargement and subsequent development of diabetic nephropathy. Secreted protein acidic and rich in cysteine (SPARC), a matricellular protein, has been shown to modulate the interaction of cells with growth factors and extracellular matrix. We have reported that primary glomerular mesangial cells derived from SPARC-null mice exhibit an accelerated rate of proliferation and produce substantially decreased levels of transforming growth factor beta1 (TGF-beta1) in comparison to their wild-type counterparts (Francki et al. [1999] J. Biol. Chem. 274: 32145-32152). Herein we present evidence that SPARC modulates IGF-dependent signaling in glomerular mesangial cells. SPARC-null mesangial cells produce increased amounts of IGF-1 and -2, as well as IGF-1 receptor (IGF-1R) in comparison to wild-type cells. Addition of recombinant SPARC to SPARC-null cells inhibited IGF-1-stimulated mitogen activated protein kinase (MAPK) activation and DNA synthesis. We also show that the observed accelerated rate of basal and IGF-1-stimulated proliferation in mesangial cells derived from SPARC-null animals is due, at least in part, to markedly diminished levels of cyclin D1 and the cyclin-dependent kinase (cdk) inhibitors p21 and p27. Since expression of SPARC in the glomerulus is especially prominent during renal injury, our findings substantiate previous claims that SPARC is involved in glomerular remodeling and repair, a process commonly associated with mesangioproliferative glomerulonephritis and diabetic nephropathy.
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PMID:SPARC regulates cell cycle progression in mesangial cells via its inhibition of IGF-dependent signaling. 1257 14

Glomerular capillary hypertension is a final common pathway to glomerulosclerosis. Because podocyte loss is an early event in the development of glomerulosclerosis, it is logical that the deleterious effects of glomerular capillary hypertension involve podocyte injury. Yet, the mechanisms by which elevated intraglomerular pressure is translated into a maladaptive podocyte response remain poorly understood. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein activated in various disease states of the podocyte and accelerates renal injury, as evidenced by the milder course of experimental diabetic nephropathy in SPARC-null mice compared with diabetic SPARC wild-type mice. Accordingly, we tested the hypothesis that mechanical strain activates SPARC in podocytes and thus is a putative mediator of podocyte injury in states of intraglomerular capillary hypertension. Conditionally immortalized mouse podocytes were subjected to 10% cyclical stretch while nonstretched cells served as controls. SPARC levels were measured in whole cell lysate and cell media. Immunostaining was performed for SPARC in an experimental model of glomerular capillary hypertension. Our results demonstrate cyclical stretch of podocytes markedly increased SPARC levels in cell lysate, through activation of p38, as well as secreted SPARC. Relevance was shown by demonstrating increased podocyte staining for SPARC in the uninephrectomized spontaneously hypertensive rat. In conclusion, we have made the novel observation that mechanical forces characteristic of states of glomerular capillary hypertension lead to increased levels of SPARC in podocytes. We speculate that the increase in SPARC may be maladaptive and lead to a progressive reduction in podocyte number, thus fueling the future development of glomerulosclerosis.
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PMID:Mechanical strain increases SPARC levels in podocytes: implications for glomerulosclerosis. 1609 28

To detect the serum concentrations of secreted protein acidic and rich in cysteine (SPARC) in patients with diabetic nephropathy and SPARC mRNA and protein expressions in renal tissue of db/db mice (C57BL/KsJ, diabetic nephropathy mice), thus preliminary exploration on the role of secreted protein acidic riches in cysteine in the development of diabetic nephropathy were carried out. Serum SPARC levels in normal subjects, patients with type 2 diabetes mellitus (without diabetic nephropathy), chronic renal failure (without diabetes mellitus), and diabetic nephropathy were determined with enzyme-linked immunosorbent assay. 12-week-old db/db mice (db/db group) and its littermate wild-type control mice (NC group) were selected with 6 from each group, and the kidney tissue were taken. RT-PCR, Western blot, and immunofluorescence were used to detect the mRNA, targeted protein expressions of SPARC and the staining of renal tissue. The serum level of SPARC in diabetic nephropathy group was significantly higher than those in normal group, type 2 diabetes mellitus, and chronic renal failure group (P < 0.05 or P < 0.01). The SPARC level in the type 2 diabetes mellitus group was higher than that in normal group (P < 0.05), but there was no difference between normal group and chronic renal failure. SPARC mRNA and protein levels in renal tissue of db/db mice were higher compared with the normal control group (P < 0.05). The long term hyperglycemic state in patients with diabetic nephropathy causes pathological change of renal tissue. Simultaneously, increased secretion of SPARC from renal tissue results in elevation of serum SPARC level. SPARC correlates with the occurrence and progression of diabetes, and it may play a role in pathological change of diabetic nephropathy.
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PMID:Correlation of secreted protein acidic and rich in cysteine with diabetic nephropathy. 2655 Jan 88