Tubular Epithelial Cell Death Research Articles

Monocyte chemoattractant protein-1 promotes macrophage-mediated tubular injury, but not glomerular injury, in nephrotoxic serum nephritis.

Monocyte chemoattractant protein-1 (MCP-1) is upregulated in renal parenchymal cells during kidney disease. To investigate whether MCP-1 promotes tubular and/or glomerular injury, we induced nephrotoxic serum nephritis (NSN) in MCP-1 genetically deficient mice. Mice were analyzed when tubules and glomeruli were severely damaged in the MCP-1-intact strain (day 7). MCP-1 transcripts increased fivefold in MCP-1-intact mice. MCP-1 was predominantly localized within cortical tubules (90%), and most cortical tubules were damaged, whereas few glomerular cells expressed MCP-1 (10%). By comparison, there was a marked reduction (>40%) in tubular injury in MCP-1-deficient mice (histopathology, apoptosis). MCP-1-deficient mice were not protected from glomerular injury (histopathology, proteinuria, macrophage influx). Macrophage accumulation increased adjacent to tubules in MCP-1-intact mice compared with MCP-1-deficient mice (70%, P < 0.005), indicating that macrophages recruited by MCP-1 induce tubular epithelial cell (TEC) damage. Lipopolysaccharide-activated bone marrow macrophages released molecules that induced TEC death that was not dependent on MCP-1 expression by macrophages or TEC. In conclusion, MCP-1 is predominantly expressed by TEC and not glomeruli, promotes TEC and not glomerular damage, and increases activated macrophages adjacent to TEC that damage TEC during NSN. Therefore, we suggest that blockage of TEC MCP-1 expression is a therapeutic strategy for some forms of kidney disease.

Apoptotic cell death in human chronic renal allograft rejection.

Chronic renal allograft rejection is characterized by gradual progression suggesting persistent low-grade injury. Apoptotic cell death may be initiated by low-grade injury secondary to external factors, making apoptosis a potential pathway of chronic rejection. In the present investigation, protocol kidney biopsies of 20 pediatric renal allograft recipients (12 with chronic rejection and 8 with normal histology), 9 pediatric liver allograft recipients, and 7 children with minimal change nephrotic syndrome were evaluated. The presence of apoptotic cell death was studied by determining apoptosis-induced oligonucleosomal DNA fragmentation in the biopsy specimens using 3' end labeling with terminal transferase, gel fractionation, and Southern blotting. The specific cell types with increased DNA fragmentation were determined by in situ 3' end labeling performed on sections of the biopsies. Significant DNA fragmentation was found only in the specimens from patients with chronic rejection. In situ investigation revealed increased apoptosis of both proximal and distal tubular epithelial cells, but not in the glomeruli or interstitium. The mean number of apoptotic tubular epithelial cells per 400x magnified field was higher in the renal allografts than in kidneys of liver transplant recipients or patients with minimal change nephrotic syndrome (2.3 vs. 0.8, P<0.05, in both cases). Our data provide biochemical evidence of increased apoptotic cell death of renal tubular epithelial cells in patients undergoing chronic renal allograft rejection.

The aging male rat: Structure and function of the kidney

The progression of anatomic and functional changes that occur with aging in normal male Sprague-Dawley rats was investigated. Renal function studies were followed by vascular perfusion fixation of the kidneys. The kidneys were examined with light microscopy and scanning and transmission electron microscopy. The glomerular filtration rate of 12-month-old rats (0.30 +/- 0.06 ml/min/100 gm body weight) was significantly lower (P less than .05) than the rates of the 3-month-old (0.91 +/- 0.08 ml/min/100 gm body weight) and 5-month-old (0.99 +/- 0.16 ml/min/100 gm body weight) rats. Urine protein levels were moderately elevated in 12-month-old rats. Structural changes mainly involved the renal corpuscle and proximal tubule. The parietal layer of Bowman's capsule was transformed from a squamous to a columnar epithelium resembling that of the proximal tubule in 48% of the capsules surveyed in 12-month-old rats. This value was significantly higher (P less than .05) than that of the 5- (14%) or 3- (6%) month-old rats. Thin sheets of cytoplasm extended from podocytic cell bodies over the layer of pedicels. The proximal tubule displayed focal areas of cell injury and necrosis. Basement membranes associated with the renal corpuscle, glomerulus, and proximal tubule were considerably thickened in the oldest group of rats. Some cellular infiltration occurred in the interstitium. Therefore, kidneys of aging Sprague-Dawley rats exhibited capsular metaplasia, death, and injury of proximal tubular epithelial cells, and other structural changes not seen in younger animals. Some of these changes may underlie the functional deterioration of their kidneys.