Induction of Renal Tubular Cell Apoptosis in Focal Segmental Glomerulosclerosis

Abstract

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.

Mitochondria Are the Major Targets in Albumin-Induced Apoptosis in Proximal Tubule Cells

“…A body of evidence accumulated from in vivo and in vitro protein overload systems indicates that albumin induces inflammatory and fibrogenic response in human proteinuric states. Tubule cell apoptosis induced by albumin has been proposed as a potential mechanism to explain the extensive tubular atrophy reported in chronic glomerular diseases (18,19).…”

“…Apoptosis was an independent predictor of ESRD. Examination of proliferation by proliferating cell nuclear antigen staining has demonstrated predominance of apoptosis over proliferation in kidney epithelial cells (18). Albumin exposure was shown to cause a mitogenic effect in wild-type opossum kidney cells via phosphatidylinositol 3-kinase, and this was inhibited by wortmannin and ⌬p85 expression (26).…”

“…In our previous studies, we showed the presence of tubule cell apoptosis in correlation with the degree of proteinuria in kidney biopsy specimens of patients with FSGS. An association between progression and tubular apoptosis was also identified (18). In an in vitro model of albumin overload, high concentrations of albumin mimicking the nephrotic milieu, proximal and distal tubule cells underwent apoptosis (19).…”

PKC-δ Promotes Renal Tubular Cell Apoptosis Associated with Proteinuria

“…[1][2][3][4] Tubular cell apoptosis has been demonstrated during albumin treatment of cultured renal tubular cells, in proteinuric animal models and also in human patients with nephrotic syndromes. [5][6][7][8][21][22][23] Although both extrinsic and intrinsic pathways of apoptosis have been shown to contribute to tubular apoptosis during proteinuria, 5-7 recent studies have further suggested the involvement of ER stress. 8 Despite these findings, very little is known about the upstream signaling that leads to the activation of the apoptotic pathways.…”

“…5 These in vitro observations were later shown to be relevant to renal tubular apoptosis associated with proteinuria in kidney biopsy specimens from children with focal segmental glomerulosclerosis. 6 However, in HKC-8 human proximal tubular cells, albumin-induced apoptosis was shown to be mainly mediated by the intrinsic pathway of apoptosis, characterized by Bax translocation to mitochondria and cytochrome c release from the organelles. 7 In addition, Ohse et al 8 demonstrated endoplasmic reticulum (ER) stress in albumin-treated rat kidney proximal tubular cells and proteinuric kidneys of puromycin aminonucleoside-treated rats, suggesting the involvement of ER stress in tubular apoptosis.…”