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Downregulation of Bcl-2 by Podocytes Is Associated with Progressive Glomerular Injury and Clinical Indices of Poor Renal Prognosis in Human IgA Nephropathy

Lian-Qun Qiu^*, Raja Sinniah and Stephen I-Hong Hsu^,

Departments of *Pathology and Medicine, Faculty of Medicine, the National University of Singapore, Singapore; Genome Institute of Singapore, Singapore; and Department of Anatomical Pathology, Royal Perth Hospital, University of Western Australia, Australia.

Correspondence to Dr. Stephen I-Hong Hsu, Department of Medicine, National University Hospital, 5 Lower Kent Ridge Road, Singapore 119074. Phone: 65-6772-4370; Fax: 65-6779-4112;

ABSTRACT. Bcl-2 defines a new class of proto-oncogenes that block cell death without promoting cell proliferation. To elucidate the role of Bcl-2 in the development of glomerular lesions in human IgA nephropathy (IgAN), we applied immunohistochemistry coupled with in situ hybridization to detect the expression of Bcl-2 products and their association with Bax, p27^kip1, and p57^kip2 in modulating the apoptotic, proliferative, and sclerotic events in progressive glomerular injury. Glomerular cell apoptosis was examined by TdT-mediated dUTP-biotin nick-end labeling (TUNEL) staining. A total of 51 IgAN cases were categorized into four subgroups (A to D) according to the severity of their histopathological lesions. Creatinine levels, creatinine clearance, and magnitude of proteinuria based on 24-h urine collections at the time of diagnostic renal biopsy were available for the majority of subjects. Bcl-2 expression was observed predominantly in podocytes in IgAN. Podocyte expression of Bcl-2 was found to be upregulated in early-stage disease and downregulated in late-stage disease. Bcl-2 downregulation in progressive IgAN was associated with an increased Bax/Bcl-2 ratio in glomerular epithelial cells and correlated with the downregulation of high endogenous podocyte p27^kip1 and p57^kip2 expression. Bax/Bcl-2 ratios positively correlated with glomerular cell apoptosis and the degree of glomerulosclerosis, whereas p27^kip1 and p57^kip2 expression levels were inversely correlated with mesangial hypercellularity and glomerulosclerosis. Clinicopathologic correlations demonstrated that downregulation of Bcl-2 protein expression was associated with indices of poor renal prognosis in human IgAN. The results suggest that Bcl-2 expression by podocytes may exert modulatory effects on cellular processes that contribute to progressive glomerular injury and play an important role in determining renal outcome in human IgA nephropathy. E-mail: mdchsus@nus.edu.sg

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673