Expression and cellular localisation of renal endothelin-1 and endothelin receptor subtypes in autosomal-dominant polycystic kidney disease.
The major factors influencing the rate of progression of chronic renal disease in autosomal-dominant polycystic kidney disease (ADPKD) are unknown and there are currently no effective treatments for slowing the progression of chronic renal failure in ADPKD patients. As a first step in investigating the potential role of endothelin-1 (ET1) and its receptors (ETA and ETB) in the pathophysiology of progression in ADPKD, we have studied their expression and cellular localisation in ADPKD kidney. Immunoreactive ET1 was detected in cyst epithelia, mesangial cells and vascular smooth muscle cells suggesting continuing ET1 synthesis in the cystic kidney. Compared to healthy controls, ETA mRNA was 5-10-fold higher in ADPKD cystic kidney. In cystic kidney, neo-expression of ETA receptors was found overlying glomeruli and cysts and markedly increased in medium-sized renal arteries by microautoradiography. This is the first study to demonstrate a specific upregulation of ETA receptors in human renal disease. Future studies should address whether ETA selective antagonists may be effective in slowing renal disease progression in ADPKD.
Ong
Albert C M
AC
Sheffield Kidney Institute, Section of Human Metabolism, Division of Clinical Sciences (NGH), University of Sheffield, London, UK. a.ong@sheffield.ac.uk
Newby
Linda J
LJ
Dashwood
Michael R
MR
D000368:Aged; D018450:Disease Progression; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005920:Glomerular Mesangium / Q000098:blood supply / Q000737:chemistry / Q000473:pathology / Q000502:physiology; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000737:chemistry / Q000473:pathology / Q000601:surgery; D007678:Kidney Glomerulus / Q000098:blood supply / Q000737:chemistry / Q000473:pathology / Q000502:physiology; D007684:Kidney Tubules / Q000098:blood supply / Q000737:chemistry / Q000473:pathology / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000473:pathology / Q000502:physiology; D009392:Nephrectomy; D009928:Organ Specificity; D016891:Polycystic Kidney, Autosomal Dominant / Q000737:chemistry / Q000378:metabolism* / Q000601:surgery; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology
D019332:Endothelin-1; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin