Physiology Topics
Autosomal dominant polycystic kidney disease is the most common cause of renal failure. In addition to renal manifestations, PKD also causes bicuspid aortic valve abnormalities, mitral valve prolapse, berry aneurisms, thoracic aortic aneurism, hypertension, pancreatic and hepatic cysts and colonic diverticuli. It may also cause renal stones.
Cysts may arise from any nephron segment (1-2% of nephrons), even in utero. This process requires an abnormal proliferative response by the renal epithelium and an abnormal sorting of proteins to the basolateral membrane.
There is a 50% probability to inhere the disease from either parent if they are carriers. The condition seems to arise from three genetic loci: 4, 16, and one unknwon loci. The loci in chromosome 16 accounts for 87% of PKD cases.
540 kb in chromosome 16, a complex region rich in G-C pairs (87%, i.e. high error rate possible), with 45 intron/exon boundaries, code for the protein polycystin. Amoung other structures, this protein has cysteine and leucine domains at the N-terminus that like to stick to other proteins outside the cytosol. It also contains an REJ module similar to the one in sea urchin sperm that allos the sperm to open a pore in ova for Ca2+ influx.
Kidneys normally develop from two embryonic tissues: mesenchyme and the ureteric bud. The glomerulus and tubule undergo a very complicated development patern from mesenchyme, and polycistin may have a role controlling their development. The collecting tube develops from the ureteric bud.
There is also evidence of altered Golgi function in kidney epitelial cells that prevents the correct allocation of proteins to the basolateral membrane. The basolateral membrane of kidney epithelial cells is biochemically and physiologically different from the apical membrane, almost like two different organelles. Proteins destined for the basolateral membrane seem to get stuck int he cysternae of the Golgi, were glycosilation occurs (abnormally in PKD). The cells end up having the wrong polarity regarding Na+/K+ ATPases, desmosomal proteins, Na+/K+/2Cl- transporters, CHIP water channels (?) and other porteins.
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