In order to find a relationship between ductal hyperplasia and carcinoma of the pancreas, histological and histochemical examinations were made on pancreatic specimens of 1,174 autopsy patients with special attention to the age incidence of the former. Ductal hyperplasia was divided into 3 types; nonpapillary, papillary, and atypical hyperplasia. All three types of hyperplasia and ductal carcinoma showed a similar tinctorial property in mucous histochemistry. In general, atypical hyperplasia was seen in the pancreas having papillary hyperplasia which was found in the pancreas associated with nonpapillary hyperplasia. All three types of hyperplasia were apparently more frequent in cancerous pancreases than in non-cancerous ones. They were also more common in the head of the pancreas than in the body and tail. Age incidence also suggests a sequential change from nonpapillary hyperplasia through papillary and atypical ones to carcinoma.Cancer 43:1418-1428, 1979.HE GREAT MAJORITY of carcinomas of the T exocrine elements of the pancreas is of duct cell rigi in.^,^ The relationship of pancreatic duct hyperplasia to pancreatic carcinoma has been emphasized by Sommers et al.," because of the high incidence of ductal hyperplasia in carcinomatous pancreases. Cubilla and Fitzgerald3 also found a similar relation. However, following Birnstingl's report, they noted that there was obstruction to the pancreatic duct in most of their cases, a complicating factor in the assessment of ductal papillary hyperplasia. Birnstingl,2 in cases with a variety of acute and chronic nonpancreatic diseases and. no cancer of the pancreas, reported an incidence of 29% having hyperplastic columnar epithelium. It seems to be necessary for clarification of the relationship between ductal hyperplasia and carcinoma of the pancreas to reevaluate the age incidence of ductal hyperplasia in noncancerous pancreases. If ductal hyperplasia is a change preceding pancreatic carcinoma, it should appear in younger patients than those with pancreatic carcinoma. The aim of the present study is to find possible From the 2nd Department of Pathology, Nagoya University School of Medicine, Nagoya, Japan.Address for reprints: S. Komka, MD, T h e 2nd Department of Pathology, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466, Japan.Accepted for publication May 22, 1978. transition from ductal hyperplasia to carcinoma by histology and mucous histochemistry and to study age difference in incidence between ductal hyperplasia and pancreatic carcinoma. MATERIALS AND METHODSUsing autopsy cases at our laboratory, available routine microscopic sections of 1,174 pancreases of which 24 had infiltrating carcinoma were examined. Mostly one section, sometimes two or more sections, was prepared from one pancreas. Selected cases were stained with periodic acid Schiff/alcian blue pH 2.5 and high iron diamine/alcian blue pH 2.5.'*"Ductal hyperplasia was defined as ducts with large epithelial cells which are more than twice as tall as normal cells, because en...

5 cells for VEGF protein; P < 0.05 both) but not by high L-glucose. It is interesting that hydrogen peroxide also blunted this response, whereas ␣-tocopherol restored the VEGF response to hypoxia in the presence of high D-glucose. For determination of involvement of the hypoxia-inducible factor (HIF)/hypoxia-responsible element (HRE) pathway, IRPTC that were stably transfected with HREluciferase were cultured under the previous conditions. High D-glucose also reduced luciferase activity under hypoxia, whereas ␣-tocopherol restored activity. In vivo experiments using streptozotocin-induced diabetic rats confirmed that hyperglycemia blunted HIF-HRE pathway activation. Insulin treatment restored activation of the HIF-HRE pathway in streptozotocin-induced diabetic rats. In conclusion, high glucose blunts VEGF response to hypoxia in IRPTC. This effect is mediated by the oxidative stress-regulated HIF-HRE pathway.

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Our studies demonstrated a crucial role of HIF in the renal medulla under normal and hypoxic circumstances.

Lipotoxicity plays an important role in the progression of chronic kidney damage via various mechanisms, such as endoplasmic reticulum stress. Several studies proposed renal lipotoxicity in glomerular and tubular cells but the effect of lipid on renal erythropoietin (EPO)-producing (REP) cells in the interstitium has not been elucidated. Since renal anemia is caused by derangement of EPO production in REP cells, we evaluated the effect of palmitate, a representative long-chain saturated fatty acid, on EPO production and the endoplasmic reticulum stress pathway. EPO production was suppressed by palmitate (palmitate-conjugated bovine serum albumin [BSA]) or a high palmitate diet, but not oleic acid-conjugated BSA or a high oleic acid diet, especially under cobalt-induced pseudo-hypoxia both in vitro and in vivo. Importantly, suppression of EPO production was not induced by a decrease in transcription factor HIF activity, while it was significantly associated with endoplasmic reticulum stress, particularly transcription factor ATF4 activation, which suppresses 3'-enhancer activity of the EPO gene. ATF4 knockdown by siRNA significantly attenuated the suppressive effect of palmitate on EPO production. Studies utilizing inherited super-anemic mice (ISAM) mated with EPO-Cre mice (ISAM-REC mice) for lineage-labeling of REP cells showed that ATF4 activation by palmitate suppressed EPO production in REP cells. Laser capture microdissection confirmed ATF4 activation in the interstitial area of ISAM-REC mice treated with palmitate-conjugated BSA. Thus, endoplasmic reticulum stress induced by palmitate suppressed EPO expression by REP cells in a manner independent of HIF activation. The link between endoplasmic reticulum stress, dyslipidemia, and hypoxia may contribute to development and progression of anemia in CKD.