endothelin-1 and Kidney-Diseases--Cystic

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.

Topics: Aged; Disease Progression; Endothelin-1; Female; Gene Expression Regulation; Glomerular Mesangium; Humans; Kidney Diseases, Cystic; Kidney Glomerulus; Kidney Tubules; Male; Middle Aged; Muscle, Smooth, Vascular; Nephrectomy; Organ Specificity; Polycystic Kidney, Autosomal Dominant; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; RNA, Messenger

The human endothelin-1 (ET-1) gene under the control of its natural promoter was transferred into the germline of mice. The transgene was expressed predominantly in the brain, lung, and kidney. Transgene expression was associated with a pathological phenotype manifested by signs such as age-dependent development of renal cysts, interstitial fibrosis of the kidneys, and glomerulosclerosis leading to a progressive decrease in glomerular filtration rate. This pathology developed in spite of only slightly elevated plasma and tissue ET-1 concentrations. Blood pressure was not affected even after the development of an impaired glomerular filtration rate. Therefore, these transgenic lines provide a new blood pressure-independent animal model of ET-1-induced renal pathology leading to renal fibrosis and fatal kidney disease.

Topics: Animals; Blood Pressure; Blotting, Northern; Body Constitution; Endothelin-1; Female; Gene Expression Regulation; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Humans; Hypertension; In Situ Hybridization; Kidney Diseases, Cystic; Male; Mice; Mice, Transgenic; Nephritis, Interstitial; Organ Size; Potassium; Proteinuria; Renal Artery; Sodium