Increased importin α protein expression in diabetic nephropathy

Abstract

Importins transport kinases, transcription factors, and viral proteins into the nucleus. Since the expression of several genes is increased in diabetic nephropathy, we tested the hypothesis that importin protein expression is increased in diabetic kidneys. Immunohistochemistry and Western blotting were used in kidneys from streptozotocin-treated diabetic rats and from spontaneously diabetic Goto-Kakizaki rats. The effects of high glucose and mannose also were tested in cell culture experiments. In normal rat kidneys, importin alpha isoforms were differentially expressed in glomerular cells and tubular segments, while importin alpha1/Rch1 was expressed only in tubules and peritubular cells. In diabetic rat kidneys from both models, the importin alpha isoform expression was markedly up-regulated. Western blotting revealed strong up-regulation of importin alpha7 and minor up-regulation of other isoforms. Exposure of various cell types to high glucose or mannose (25 mmol/L) led to increased expression of importins alpha3, alpha5/hSRP1, and alpha7 in different cultured cells, while up-regulation of other importin alpha isoforms was less consistent. A specific importin alpha isoform up-regulation takes place in kidneys of diabetic rats. Diabetes is a stimulus for increased importin alpha7 expression. Thus, nuclear transport in diabetes may be increased in glomerular and tubular cells. The signaling pathways appear differentially regulated in glomeruli, proximal, and distal tubules. The enhanced nuclear transport may participate in increased gene expression and nephrosclerosis in diabetes.