gastrins and Fibrosis

Hypertensive nephropathy (HN) is a common cause of end-stage renal disease with renal fibrosis; chronic kidney disease is associated with elevated serum gastrin. However, the relationship between gastrin and renal fibrosis in HN is still unknown. We, now, report that mice with angiotensin II (Ang II)-induced HN had increased renal cholecystokinin receptor B (CCKBR) expression. Knockout of CCKBR in mice aggravated, while long-term subcutaneous infusion of gastrin ameliorated the renal injury and interstitial fibrosis in HN and unilateral ureteral obstruction (UUO). The protective effects of gastrin on renal fibrosis can be independent of its regulation of blood pressure, because in UUO, gastrin decreased renal fibrosis without affecting blood pressure. Gastrin treatment decreased Ang II-induced renal tubule cell apoptosis, reversed Ang II-mediated inhibition of macrophage efferocytosis, and reduced renal inflammation. A screening of the regulatory factors of efferocytosis showed involvement of peroxisome proliferator-activated receptor α (PPAR-α). Knockdown of PPAR-α by shRNA blocked the anti-fibrotic effect of gastrin in vitro in mouse renal proximal tubule cells and macrophages. Immunofluorescence microscopy, Western blotting, luciferase reporter, and Cut&tag-qPCR analyses showed that CCKBR may be a transcription factor of PPAR-α, because gastrin treatment induced CCKBR translocation from cytosol to nucleus, binding to the PPAR-α promoter region, and increasing PPAR-α gene transcription. In conclusion, gastrin protects against HN by normalizing blood pressure, decreasing renal tubule cell apoptosis, and increasing macrophage efferocytosis. Gastrin-mediated CCKBR nuclear translocation may make it act as a transcription factor of PPAR-α, which is a novel signaling pathway. Gastrin may be a new potential drug for HN therapy.

Topics: Angiotensin II; Animals; Apoptosis; Fibrosis; Gastrins; Humans; Hypertension; Hypertension, Renal; Jurkat Cells; Kidney Tubules, Proximal; Mice; Mice, Knockout; Nephritis; Phagocytosis; PPAR alpha; Receptors, Cholecystokinin; RNA, Small Interfering; Signal Transduction; Ureteral Obstruction

A case of duodenal somatostatinoma is described in a patient with Von Recklinghausen neurofibromatosis. The patient presented with exocrine pancreatic insufficiency, probably due to distal obstruction of the pancreatic duct by the tumor. Preoperative evaluation with calcium-pentagastrin and tolbutamide stimulation tests were nondiagnostic. At laparotomy, local excision of the tumor was performed. Pathological findings were compatible with duodenal somatostatinoma, causing pancreatic fibrosis. Somatostatin extracted from the tumor coeluted with the somatostatin-14 standard on high performance liquid chromatography (HPLC).

Topics: Adult; Biopsy; Chromatography, High Pressure Liquid; Duodenal Neoplasms; Exocrine Pancreatic Insufficiency; Female; Fibrosis; Gastrins; Glucagon; Humans; Microscopy, Electron; Neurofibromatosis 1; Pancreas; Pancreatic Polypeptide; Radioimmunoassay; Somatostatin; Somatostatinoma; Vasoactive Intestinal Peptide

A histological and immunohistological investigation was performed on biopsy specimens from ten patients 3 to 35 years after antrectomy, to study the type of epithelium and the possible occurrence of gastrin-producing cells (G cells) in the distal stump of the stomach remnant. The study showed that parietal cells were present in all patients, whereas G cells could not be demonstrated, although areas of pyloric-type epithelium (pseudopyloric metaplasia, were seen in eight. We conclude that the pyloric-type metaplasia, which occurs in the fundic mucosa after antrectomy, does not involve the G cells. It is suggested that the normal levels of fasting serum gastrin in these patients originate from outside the gastric mucosa, presumably from the duodenal bulb.

Topics: Adenocarcinoma; Biopsy; Epithelium; Fibrosis; Follow-Up Studies; Gastrectomy; Gastric Acid; Gastrin-Secreting Cells; Gastrins; Gastritis, Atrophic; Gastroscopy; Humans; Postoperative Period; Pyloric Antrum; Radioimmunoassay; Stomach Neoplasms; Stomach Ulcer; Time Factors