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CELLULAR AND MOLECULAR

Bortezomib-Induced Survival Signals and Genes in Human Proximal Tubular Cells

Division of Nephrology and Hypertension, Department of Internal Medicine IV, Innsbruck Medical University, Innsbruck, Austria (R.S., K.H., J.E., M.P., S.E., M.R., A.R.R., G.M., H.S.); and Emergentec Biodevelopment GmbH, Vienna, Austria (P.P., M.W., B.M.)

Bortezomib has been introduced recently in the therapy of multiple myeloma (MM), a disease that is frequently associated with progressive renal failure. Because bortezomib-based therapy has been reported to lead to a rapid recovery of kidney function in patients with MM, we decided to study its direct effects in proximal tubular epithelial cells (PTCs) compared with glomerular mesangial cells (GMCs). After 24 h of stimulation, 50 nM bortezomib led to a 6.37-fold induction of apoptosis and markedly activated caspase-9 and -3 in GMCs but not in PTCs. In PTCs but not in GMCs, bortezomib led to a strong time-dependent degradation of IB- and to a long-lasting phosphorylation of both NF-Bp65 and extracellular signal-regulated kinase 1/2. Microarray analysis in bortezomib-treated PTCs revealed a time-dependent predominance of antiapoptotic genes compared with proapoptotic genes. Bortezomib (50 nM) induced heat shock protein (Hsp) 70 mRNA and protein levels in PTCs, whereas basal and bortezomib-stimulated Hsp70 protein expression was much weaker in GMCs. Moreover, bortezomib induced Bcl-2-associated athanogene (BAG) 3 mRNA and protein expression but inhibited BAG5 mRNA levels in PTCs. These data suggest that the reduced susceptibility of PTCs to bortezomib-induced cell apoptosis is because of cell type-specific effects of this compound on apoptosis/survival genes and pathways. The concept of bortezomib representing a blocker of both NF-B activation and cell survival should be carefully examined in particular renal cell types.

Address correspondence to: Dr. Herbert Schramek, Department of Internal Medicine IV, Nephrology and Hypertension, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria. E-mail: herbert.schramek{at}i-med.ac.at