gastrins and Hypertension--Renal

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

High levels of serum calcitonin were found in patients with chronic renal failure. Serum calcitonin correlated directly with the phosphate to total calcium ratio; calcitonin levels correlated inversely with serum calcium in those patients on dialysis and directly with serum calcium in nondialysis patients. All patients had elevated serum gastrin. The high levels of serum calcitonin usually decreased following successful kidney transplantation. The pathophysiology of this hypercalcitonemia and its relationship to renal osteodystrophy and the disordered calcium metabolism of uremia remains to be elucidated.

Topics: Adult; Calcitonin; Calcium; Diabetic Nephropathies; Female; Gastrins; Glomerulonephritis; Humans; Hypertension, Renal; Kidney Diseases, Cystic; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Phosphates; Pyelonephritis; Renal Dialysis

Topics: Acute Kidney Injury; Erythropoietin; Gastrins; Glucose; Humans; Hypertension, Renal; Insulin; Kidney; Parathyroid Hormone; Renin; Vitamin D