Matrix metalloproteinases and mesangial remodeling in light chain-related glomerular damage

Keeling, John; Herrera, Guillermo A.

doi:10.1111/j.1523-1755.2005.00571.x

Cited by 63 publications

(57 citation statements)

References 48 publications

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“…Incubation of mesangial cells with LC from patients with LCDD induced cell changes, activation of PDGF-␤ and its receptor, production of monocyte chemoattractant protein-1, and increased expression of Ki-67, a proliferation marker, whereas tubulopathic LC had no effect (31). The resulting phenotype is close to myofibroblastic phenotype, including activation of ECM synthesis and decreased matrix metalloproteinase production and activity (26,32) (Figure 2). In contrast, mesangial cells that are incubated with LC from patients with AL-amyloidosis undergo a macrophage-like transformation, with increased matrix metalloproteinase activity and decreased ECM production (32).…”

Section: Pathophysiology Of Ecm Accumulationmentioning

confidence: 98%

“…Tenascin is an ECM protein that is a component of the mesangium in normal and, most important, in pathologic conditions (28). Tenascin was shown to accumulate in the center of mesangial nodules in patients with LCDD and nodular glomerulosclerosis (26). Tenascin production by mesangial cells is enhanced in the in vitro model (29) as well as in patients with LCDD.…”

Section: Pathophysiology Of Ecm Accumulationmentioning

confidence: 99%

“…Nodules are made of normal constituents (collagen type IV, laminin, fibronectin, and tenascin) (25,26) and stain weakly for the small proteoglycans decorin and biglycan (27). Tenascin is an ECM protein that is a component of the mesangium in normal and, most important, in pathologic conditions (28).…”

Section: Pathophysiology Of Ecm Accumulationmentioning

confidence: 99%

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Immunoglobulin Light (Heavy)-Chain Deposition Disease

Ronco¹,

Plaisier²,

Mougenot³

et al. 2006

Clinical Journal of the American Society of Nephrology

112

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Light-, light-and heavy-, and heavy-chain deposition diseases belong to a family of diseases that include light-chain (AL)-amyloid, nonamyloid fibrillary and immunotactoid glomerulonephritis, and cryoglobulinemic glomerulonephritis, in which monoclonal Ig or their subunits become deposited in kidney. In clinical and pathologic terms, light-, light-and heavy-, and heavy-chain deposition diseases essentially are similar and are characterized by prominent renal involvement with severe renal failure; extrarenal manifestations; diabetes-like nodular glomerulosclerosis; marked thickening of tubular basement membranes; and monotypic deposits of light chain, mostly , and/or heavy chain that feature a nonorganized granular, electron-dense appearance by electron microscopy. The most common cause is myeloma. Recent progress has been made in the understanding of the molecular pathomechanisms of Ig-chain deposition and extracellular matrix accumulation, which opens up new therapeutic avenues in addition to eradication of the Ig-secreting plasma cell clone. Because these diseases represent a model of glomerular and interstitial fibrosis that is induced by a single molecule species, a better understanding of their pathomechanisms may help to unravel the pathophysiology of kidney fibrosis and renal disease progression.

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Section: Pathophysiology Of Ecm Accumulationmentioning

confidence: 98%

Section: Pathophysiology Of Ecm Accumulationmentioning

confidence: 99%

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Immunoglobulin Light (Heavy)-Chain Deposition Disease

Ronco¹,

Plaisier²,

Mougenot³

et al. 2006

Clinical Journal of the American Society of Nephrology

112

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“…This hypothesis could only be confirmed by longitudinal, histological data demonstrating tissue-specific dysregulation of MMP-2, which precedes clinical nephropathy. However, intrarenal MMP-2 expression or MMP-2 activity is increased in other examples of renal pathological conditions (27,28). In addition, MMP-2 and MMP-9 are produced by cultured glomerular podocytes, and podocyte MMP production in culture can be modified by numerous growth factors, by cytokines, and by high ambient glucose levels (29 -31).…”

Section: Multiple Regression Analysismentioning

confidence: 99%

Matrix Metalloproteinase-2 Dysregulation in Type 1 Diabetes

et al. 2007

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OBJECTIVE -Dysregulation of matrix metalloproteinase (MMP)-2 may contribute pathologically to the development of diabetes complications, including diabetic retinopathy and coronary and peripheral arterial disease. Our objective was to explore whether systemic MMP-2 dysregulation could be demonstrated in type 1 diabetes and to determine how MMP-2 concentration relates to disease status.RESEARCH DESIGN AND METHODS -In this cross-sectional study, MMP-2 concentrations and MMP-2 activity were measured in plasma and timed urine samples from 93 type 1 diabetic and 50 healthy control subjects, aged 14 -40 years. Relationships between MMP-2 concentrations in these biological fluids and subject characteristics (sex, age, and duration of type 1 diabetes), indexes of glycemic control (A1C, fasting plasma glucose, and continuous glucose monitoring system average daily glucose), and measurements of renal function (urinary albumin excretion and glomerular filtration rate) were examined.RESULTS -Urine and plasma MMP-2 concentrations and plasma MMP-2 activity were all significantly elevated in type 1 diabetic subjects compared with those in control subjects. Urine MMP-2 concentrations, in particular, were correlated with several clinical parameters that infer increased risk for diabetic comorbidity and specifically for diabetic nephropathy, including higher A1C, longer duration of disease, evidence of renal hyperfiltration, and the presence of microalbuminuria.CONCLUSIONS -Urine and plasma MMP-2 concentrations are dysregulated in type 1 diabetes; urinary excretion of MMP-2, in particular, might provide a unique biomarker of diabetes-induced intrarenal pathologic processes. Diabetes Care 30:2321-2326, 2007M atrix metalloproteinases (MMPs) constitute a group of enzymes that hydrolyze protein components of the extracellular matrix (1). The subgroup of MMPs known as gelatinases, specifically gelatinase A (MMP-2) and gelatinase B (MMP-9) digest collagen, denatured collagens (i.e., gelatins), laminin, elastin, and fibronectin, among other substrates (2), and have been implicated in the pathological processes that contribute to fibrotic diseases, tumor progression, and inflammation (1,3,4).Dysregulation of gelatinase activity has also been implicated in the pathophysiology of diabetes complications. Specifically, gelatinase concentrations are increased in the systemic circulation ) and in the vitreous (MMP-2 [6] and MMP-9 [7]) of type 1 diabetic patients with diabetic retinopathy. Elevated retinal levels of MMP-2 and MMP-9 have also been demonstrated in an animal model of diabetic retinopathy (8). Increased circulating concentrations of MMP-2 have been observed in pediatric patients with type 1 diabetes who developed microangiopathy over a 5-year interval (9). Systemic concentrations of MMP-2 and MMP-9, in addition to gelatinase activity levels, are also increased in patients with type 2 diabetes and peripheral arterial disease (10).Data suggesting a link between MMP-2 dysregulation and diabetic nephropathy also exist but appear contra...

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“…This process; however, occurs slowly and in the early phases of this disease the replacement of normal mesangium may be very focal and segmental. The increased mesangial deposition of amyloid serves to further enhance apoptosis of mesangial cells which also occurs as a direct consequence of the amyloidogenic light chains [26][27][28][29][30]. Amyloidosis is characteristically associated with lambda light chains and glomerular amyloid is generally derived from λ6 light chains [31,32].…”

Section: What Are the Morphologic Parameters That Allow To Make A Diamentioning

confidence: 99%