Members of the bcl-2 family of proteins regulate the occurrence of apoptotic cell death. Apoptosis is a feature of both acute and chronic renal diseases. Diabetes mellitus modulates renal growth; it induces acute tubuloepithelial cell hypertrophy, leads to chronic glomerulopathy associated with tubular epithelial cell atrophy and interstitial fibrosis, and predisposes to renal cell loss from acute nephrotoxic injury. However, the mechanisms by which diabetes affects renal cell turnover are unclear. Northern analysis was performed on RNA isolated from murine tubular epithelial MCT cells grown in a medium with physiological or high glucose concentration (5.5 or 25 mmol/L, respectively) for 24 to 96 hours, and from kidney cortex of spontaneously diabetic db/db mice and their nondiabetic db/m littermates. Counting of dead cells in tissue culture and in the renal cortex was also carried out. High ambient glucose downregulated the expression of the bcl-2 gene whose protein product is protective against apoptosis. Expression of the related bclx mRNA was also downregulated. However, the level of bax mRNA that encodes an apoptosis-promoting protein was transiently increased. Hyperosmolarity induced by D-mannitol did not reproduce these effects of high glucose. High glucose significantly increased the number of dead cells in culture. Thus, the net effect of high glucose concentration is to increase the expression of apoptosis regulatory genes and to favor apoptosis in proximal tubular epithelial cells. Correlative studies in vivo revealed decreased bcl-2 and increased bax gene expression in the renal cortex of diabetic db/db mice, and this was associated with increased apoptotic index in the tubular epithelium as compared with nondiabetic littermates. These studies suggest that the metabolic changes of the diabetic state modulate the expression of apoptosis-regulatory genes so as to favor apoptosis and that this modulation may be a factor in the pathogenesis of diabetic nephropathy.