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Proteinuria and glomerular damage
ABSTRACTS
1 Diab Comp 1992; 6:4
265
ABSTRACTS
PROTEINURIA
AND GLOMERULAR
DAMAGE
T. Bertani and G. Remuzzi Mario Negri Institute of Pharmacological Research, 24100 Bergamo, Italy Objective: To verify the possibility that abnormal transit of plasma proteins through the glomerular capillary membrane plays a major role in the subsequent development of glomerulosclerosis in experimental and human nephropathies. Design and Setting: Renal diseases with altered glomerular permselective properties are reviewed; these include diabetes mellitus in experimental animals and humans, aging in rats, adriamycin and puromycin nephrosis in rats, overload proteinuria in rats. Results: Evidence is presented that, in the conditions considered, abnormal permeability to proteins correlates with the development of focal and segmental glomerulosclerosis and that maneuvers that restore glomerular permselective properties such as the use of angiotensin-converting enzyme (ACE) inhibitor, prevent the evolution of the disease to glomerulosclerosis. Once glomerular permselective properties have been disrupted, mesangial cells exposed to an abnormal protein traffic may proliferate and synthesize mesangial matrix in excessive amounts. Similarly, glomerular epithelial cells undergo structural and functional modifications, including focal detachment from basement membrane, with further increase of the passage of macromolecules across the glomerular capillaries. This results is an increased amount of proteins in the ultrafiltrate that overwhelms proximal tubular epithelial cell reabsorption capacity. This leads to interstitial inflammatory reaction mainly due to interstitial infiltration of T lymphocytes and macrophages that release factors that may play a major role in the subsequent development of sclerotic process. Recently, investigators have found in experimental animals with nephrotic syndrome that, in association with tubulo-interstitial inflammatory reaction, a macrophage-derived lipid chemotactic factor is present in the urine. Evidence has been presented that such factor is produced by proximal tubular cell after endocytosis of albumin.
Filtered proteins are extensively reabConclusions: sorbed by tubular proximal epithelium, and such a process implies incorporation of proteins into endocytotic vesicles. Excessive accumulation of proteins in proximal tubular cells leads to cellular damage and interstitial accumulation of circulating proteins and lipids. The subsequent interstitial nephritis precedes, and determines in some models, the evolution of the disease toward glomerulosclerosis.
NEPHROTOXICITY OF PROTEINS 1. J. Weening Department of Pathology, University of Amsterdam, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Under normal conditions most serum Introduction: proteins cannot pass the glomerular capillary wall (GCW) and do not reach the urinary space, because of the efficient size- and charge-selective filter function of the GCW. Low molecular weight proteins may reach the outer side of the GCW, are endocytosed by the glomerular epithelial cells and may eventually enter the urinary space. Most of the filtered proteins are then taken up by the tubular epithelial cells in the normal process of reabsorption and are subsequently catabolized by intracellular lysosomal enzymes. Under pathologic conditions, such as an excessive increase in the concentration of circulating proteins, e.g., in dysproteinemias, or when the GCW has been become leaky in the process of glomerular injury, the load of filtered proteins may increase and may lead to functional and structural alterations of the glomerulus and tubules. Dysproteinemias: Glomerular pathology in dysproteinemias includes mesangial accumulation of proteins associated with hypercellularity and increased matrix production. Deposition of immunoglobulins along the GCW may lead to light chain nephropathy. A well-known complication of dysproteinemias in amyloidosis, which often involves the glomerulus and may lead to massive proteinuria. More frequent in dysproteinemias is tubulointerstitial involvement, associated with varying degrees of
1 Diab Comp 1992; 6:4
265
ABSTRACTS
PROTEINURIA
AND GLOMERULAR
DAMAGE
T. Bertani and G. Remuzzi Mario Negri Institute of Pharmacological Research, 24100 Bergamo, Italy Objective: To verify the possibility that abnormal transit of plasma proteins through the glomerular capillary membrane plays a major role in the subsequent development of glomerulosclerosis in experimental and human nephropathies. Design and Setting: Renal diseases with altered glomerular permselective properties are reviewed; these include diabetes mellitus in experimental animals and humans, aging in rats, adriamycin and puromycin nephrosis in rats, overload proteinuria in rats. Results: Evidence is presented that, in the conditions considered, abnormal permeability to proteins correlates with the development of focal and segmental glomerulosclerosis and that maneuvers that restore glomerular permselective properties such as the use of angiotensin-converting enzyme (ACE) inhibitor, prevent the evolution of the disease to glomerulosclerosis. Once glomerular permselective properties have been disrupted, mesangial cells exposed to an abnormal protein traffic may proliferate and synthesize mesangial matrix in excessive amounts. Similarly, glomerular epithelial cells undergo structural and functional modifications, including focal detachment from basement membrane, with further increase of the passage of macromolecules across the glomerular capillaries. This results is an increased amount of proteins in the ultrafiltrate that overwhelms proximal tubular epithelial cell reabsorption capacity. This leads to interstitial inflammatory reaction mainly due to interstitial infiltration of T lymphocytes and macrophages that release factors that may play a major role in the subsequent development of sclerotic process. Recently, investigators have found in experimental animals with nephrotic syndrome that, in association with tubulo-interstitial inflammatory reaction, a macrophage-derived lipid chemotactic factor is present in the urine. Evidence has been presented that such factor is produced by proximal tubular cell after endocytosis of albumin.
Filtered proteins are extensively reabConclusions: sorbed by tubular proximal epithelium, and such a process implies incorporation of proteins into endocytotic vesicles. Excessive accumulation of proteins in proximal tubular cells leads to cellular damage and interstitial accumulation of circulating proteins and lipids. The subsequent interstitial nephritis precedes, and determines in some models, the evolution of the disease toward glomerulosclerosis.
NEPHROTOXICITY OF PROTEINS 1. J. Weening Department of Pathology, University of Amsterdam, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Under normal conditions most serum Introduction: proteins cannot pass the glomerular capillary wall (GCW) and do not reach the urinary space, because of the efficient size- and charge-selective filter function of the GCW. Low molecular weight proteins may reach the outer side of the GCW, are endocytosed by the glomerular epithelial cells and may eventually enter the urinary space. Most of the filtered proteins are then taken up by the tubular epithelial cells in the normal process of reabsorption and are subsequently catabolized by intracellular lysosomal enzymes. Under pathologic conditions, such as an excessive increase in the concentration of circulating proteins, e.g., in dysproteinemias, or when the GCW has been become leaky in the process of glomerular injury, the load of filtered proteins may increase and may lead to functional and structural alterations of the glomerulus and tubules. Dysproteinemias: Glomerular pathology in dysproteinemias includes mesangial accumulation of proteins associated with hypercellularity and increased matrix production. Deposition of immunoglobulins along the GCW may lead to light chain nephropathy. A well-known complication of dysproteinemias in amyloidosis, which often involves the glomerulus and may lead to massive proteinuria. More frequent in dysproteinemias is tubulointerstitial involvement, associated with varying degrees of