Induction of renal tubular cell apoptosis in focal segmental glomerulosclerosis: roles of proteinuria and Fas-dependent pathways.
The hypothesis that apoptosis represents a proximate mechanism by which tubule cells are damaged in FSGS was tested. Thirty kidney biopsy specimens from children with idiopathic early FSGS were studied retrospectively. Unexpected, apoptosis was evident in both proximal and distal tubule cells. There was a significant correlation between the degree of proteinuria and the number of apoptotic cells. Fas protein was detected predominantly in the tubule cells that underwent apoptosis. When compared with patients with other chronic proteinuric states, those with FSGS displayed a proliferation/apoptosis ratio in favor of proliferation in the glomerulus but dramatically in favor of apoptosis in the tubules. When both proteinuria and apoptosis were included in a stepwise logistic regression procedure, only apoptosis was found to predict independently the development of ESRD. Prolonged incubation of cultured Madin-Darby canine kidney (distal/collecting) cells with albumin also resulted in a dose- and duration-dependent induction of apoptosis and activation of the Fas pathway, lending support to the novel finding of distal tubule cell apoptosis in patients with FSGS. The results indicate that an elevated tubule cell apoptosis rate at the time of initial biopsy represents an independent predictor of progression to ESRD in patients with early FSGS.
Erkan
Elif
E
Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
Garcia
Clotilde D
CD
Patterson
Larry T
LT
Mishra
Jaya
J
Mitsnefes
Mark M
MM
Kaskel
Frederick J
FJ
Devarajan
Prasad
P
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001707:Biopsy, Needle; D015153:Blotting, Western; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D015331:Cohort Studies; D018450:Disease Progression; D004285:Dogs; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D007676:Kidney Failure, Chronic / Q000473:pathology*; D007684:Kidney Tubules / Q000473:pathology* / Q000648:ultrastructure; D016015:Logistic Models; D008297:Male; D011336:Probability; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D019014:fas Receptor / Q000378:metabolism*
D019014:fas Receptor