The aim of the present study was to investigate the role of the endoplasmic reticulum stress and apoptosis in experimental diabetic nephropathy. The effects of ACE inhibitor on the endoplasmic reticulum stress and apoptosis were also assessed. Diabetes was induced in male Sprague-Dawley rats by injection with streptozotocin at 60 mg/kg i .p. Diabetic rats were then randomly assigned into control (untreated) or treatment of an ACE inhibitor, perindopril, for 24 weeks. Tubulointerstitial injury was assessed by histopathology. Tubule apoptosis was detected by TUNEL assay. Endoplasmic reticulum stress associated proteins expression of glucose-regulated protein-78 (GRP78/BiP), phospho-eukaryotic initiation factor 2 alpha (eIF2 alpha), phospho-pancreatic ER kinase (PERK) and caspase-12 was assessed by immunohistochemistry and Western blots. There were more TUNEL-positive nuclei in diabetic kidneys than in control kidneys. At 24 weeks, experimental diabetes was associated with a considerable increase in protein expression of GRP78, phospho-eIF2 alpha, phospho-PERK, and caspase-12 in the tubulointestitium. ACE inhibitor not only attenuated the apoptosis but also reduced the overexpression of these endoplasmic reticulum stress associated proteins in tubulointestitium of diabetic rats. Increased tubular apoptosis in experimental diabetic rats is attenuated by blockade of the renin-angiotensin system with an ACE inhibitor, which might be in an association with reduced endoplasmic reticulum stress.