THE ETIOLOGY, PATHOGENESIS, AND TREATMENT OF AUTOSOMAL-DOMINANT POLYCYSTIC KIDNEY-DISEASE - RECENT ADVANCES

Autosomal dominant polycystic kidney disease (ADPKD) is caused by muta tions in at least three different genes: PKD1, PKD2, and PKD3. ADPKD1 is an inherited disorder that has led to the discovery of a novel prot ein, polycystin, Polycystin, a 460 kd protein with a host of domains i mplicating a potential role in cell-cell and cell-matrix regulation, i s encoded by a 52 kb gene with a 14 kb mRNA. The PKD2 protein is also large (110 kd) and is thought to interact with polycystin, ADPKD1 is c aused by mutated DNA that encodes an abnormal form of polycystin. Poly cystin appears to have a normal role in the differentiation of epithel ial cells, and when defective, these cells fail to maturate fully, The se incompletely differentiated cells proliferate abnormally and expres s altered amounts of otherwise normal electrolyte transport proteins t hat result in excessive secretion of solute and fluid into the cysts, The proliferation of ?he cells and the associated apoptosis, end the s ecretion of the fluid into the cysts created by the enlarging tubule s egments appear to be regulated by growth factors, hormones, and cytoki nes that can alter the extent to which the disease is clinically expre ssed among individuals, The formation of the cysts is associated with complex changes in the extracellular matrix of the kidneys and other o rgans that may be directly or indirectly tied to mutated polycystin, T he summation of these pathogenetic elements leads to renal interstitia l infiltration, with monocytes, macrophages, and fibroblasts culminati ng in fibrosis and progressive loss of renal function, The modern unde rstanding of cyst pathogenesis opens opportunities to develop treatmen ts that may diminish or halt altogether the progression of this diseas e. (C) 1996 by the National Kidney Foundation, Inc.