Up-regulation of clusterin (sulfated glycoprotein-2) in pancreatic islet cells upon streptozotocin injection to rats

Abstract

Clusterin is a heterodimeric glycoprotein which has been shown to play important roles in programmed cell death and/or in tissue reorganization not only during embryonic development but also in damaged tissues. Recently, we reported the transient induction of clusterin in pancreatic endocrine cells during early developmental stages of islet formation. In the present study, we have investigated the expression of clusterin in pancreatic tissue of streptozotocin-treated rats which were undergoing extensive islet tissue reorganization due to degeneration of insulin cells. Clusterin was found in endocrine cells identified as glucagon-secreting cells at the periphery of the islet. Using immunoelectron microscopy, clusterinpositive cells showed the typical ultrastructural features of pancreatic cells. In addition, colocalization of clusterin and glucagon in the same secretory granules was shown by double immunogold labeling. These results imply that clusterin is a secretory molecule having endocrine and/or paracrine actions in parallel with glucagon. Further, we noted that clusterin expression was increased in pancreatic cells during the process of cell death upon streptozotocin injection. The increase was significant as early as 1-3 h after streptozotocin treatment prior to any morphological alteration of islet cell and any manifestation of hyperglycemia. The expression of clusterin was steadystately up-regulated during the process of islet reorganization caused by streptozotocin-induced cytotoxic injury. Therefore, we suggest that clusterin might be considered as a molecule induced by both embryonic development and drug-induced reorganization of the endocrine pancreas. Since clusterin expression is up-regulated in cells, but not in cells undergoing degeneration, it may play a protective role against the cytotoxic insult.

Clusterin expression during regeneration of pancreatic islet cells in streptozotocin-induced diabetic rats

“…Clusterin immunoreactivity was confined to alpha cells. As we previously reported [7], it was weakly detected in tissues of normal adult rats but increased in islets upon streptozotocin treatment in the early stage of the experi- , J) and immunocytochemistry (C±H, K, L) in group 1 (A±D), group 2 (E±H) and group 3 (I±L). In group 1 and 3, cell population and intensity of reaction signals for insulin and clusterin showed a remarkable increase at 5 weeks in most cases (B, D, J, L) when compared with those of normal control rats (C) or at 1 week after streptozotocin treatment (A, I, K).…”

“…Clusterin was also up-regulated in pancreatic cells in response to streptozotocin injection particularly in the surviving alpha cells, which reflected its cytoprotective role. Furthermore, we noted a higher expression of clusterin in islets at the initiation of islet reconstruction upon extensive destruction by streptozotocin treatment [7]. Therefore, besides being involved in cell protection, we postulated that clusterin might participate in islet reorganization during or after the onset of diabetes as a growth factor-like molecule.…”

“…Clusterin is known to be up-regulated at sites of tissue remodelling through differentiation and proliferation after apoptosis [10,14,16,41]. We have reported the expression of clusterin in the developing pancreas and in the pancreatic tissue of the streptozotocin treated rats and suggested that this protein must play important roles [7,20]. Therefore, we examined whether the expression of clusterin is associated with islet-cell replication and with islet reorganization in diabetic animal models.…”

“…Western blot analysis was done as described previously [7]. Briefly, pancreatic tissue samples were homogenized in lysis buffer (25 mmol/l Tris-HCL, pH 7.4, 1.0 mmol/l EDTA, 0.5 % Triton X-100) with a Dounce homogenizer.…”

An expression profile of human pancreatic islet mRNAs by Serial Analysis of Gene Expression (SAGE)

“…While its expression was increased in regenerating pancreas, suggesting one of its names, its actual role as a proliferation factor for islets is currently unclear [31]. Even though clusterin has been described to be expressed in both exocrine [32] and endocrine cells [33] during cell injuries, its expression in our libraries seemed restricted to the islets.…”