Coordinate Expression of the Autosomal Dominant Polycystic Kidney Disease Proteins, Polycystin-2 And Polycystin-1, in Normal and Cystic Tissue

Abstract

A second gene for autosomal dominant polycystic kidney disease (ADPKD) , PKD2, has been recently identified. Using antisera raised to the human PKD2 protein , polycystin-2 , we describe for the first time its distribution in human fetal tissues , as well as its expression in adult kidney and polycystic PKD2 tissues. Its expression pattern is correlated with that of the PKD1 protein , polycystin-1. In normal kidney, expression of polycystin-2 strikingly parallels that of polycystin-1 , with prominent expression by maturing proximal and distal tubules during development, but with a more pronounced distal pattern in adult life. In nonrenal tissues expression of both polycystin molecules is identical and especially notable in the developing epithelial structures of the pancreas, liver , lung , bowel , brain , reproductive organs, placenta , and thymus. Of interest , nonepithelial cell types such as vascular smooth muscle , skeletal muscle , myocardial cells , and neurons also express both proteins. In PKD2 cystic kidney and liver , we find polycystin-2 expression in the majority of cysts, although a significant minority are negative , a pattern mirrored by the PKD1 protein. The continued expression of polycystin-2 in PKD2 cysts is similar to that seen by polycystin-1 in PKD1 cysts , but contrasts with the reported absence of polycystin-2 expression in the renal cysts of Pkd2؉/؊ mice. These results suggest that if a two-hit mechanism is required for cyst formation in PKD2 there is a high rate of somatic missense mutation. The coordinate presence or loss of both polycystin molecules in the same cysts supports previous experimental evidence that hetero- Renal cysts are the primary cause of morbidity in autosomal dominant polycystic kidney disease (ADPKD) but it is evident that the disease phenotype extends beyond the kidney. Cysts are commonly found in the liver and pancreas and have been reported in testis, spleen, ovary, uterus, esophagus, and brain. Moreover, abnormalities suggestive of a generalized disorder of connective tissue, including cardiac valvular abnormalities (especially mitral valve prolapse), intracranial berry aneurysms, colonic diverticulae, inguinal hernia, and a family with Marfanoid habitus, have been described. 1,2 Mutations in two genes, PKD1 and PKD2, account for the vast majority of patients with ADPKD. The identification of these genes 3,4 has thus provided a new opportunity to study the pathophysiology of ADPKD. The predicted proteins appear quite different in structure (the PKD1 protein, polycystin-1, is ϳ4 times larger than its counterpart, polycystin-2 4,5 ). Nonetheless, they share a significant region of homology in their transmembrane regions, an area also similar to a family of voltage-gated calcium/sodium channels. 4,6 Recent evidence indicates that the ADPKD proteins may interact in experimental systems. 7,8 PKD2 is less prevalent than PKD1, accounting for ϳ15% of ADPKD cases, 9,10 but preliminary evidence suggests they share the same spectrum of extrarenal manifestations. In one st...

Human ADPKD primary cyst epithelial cells with a novel, single codon deletion in the PKD1 gene exhibit defective ciliary polycystin localization and loss of flow-induced Ca2+ signaling

“…A recent report appearing after completion of the work presented here extended this observation to human ADPKD cyst cells expressing little or no PC1 polypeptide (31). However, human ADPKD is almost always characterized by normal or increased renal levels of apparently full-length PC1 polypeptide (32,36,37), despite the significantly truncated proteins encoded by most PKD1 germline mutations (35). Indeed, phenotypically similar murine polycystic kidney disease (PKD) results from knockout and from overexpression of the wild-type pkd1 gene (44,60).…”

Pkd1-inactivation in vascular smooth muscle cells and adaptation to hypertension

“…It is known that Pkd1 is also expressed in pancreatic ducts, hepatic bile ducts and Bowman's capsule, and thus coincides with the origin of the cysts as well. 5,35,36 These cysts can be found in ADPKD patients as well. Our data indicate that the SM22 promoter fragment that regulates the expression of Cre is not exclusively expressed in vascular SMCs.…”

c-Myc Signalling in the Genetic Mechanism of Polycystic Kidney Disease

“…In ADPKD patients, expression levels of the PKD1/PKD2 mutated allele can be strongly or mildly reduced. Paradoxically, PKD1/PKD2 and PC1/PC2 are found overexpressed in human ADPKD kidneys (3,(62)(63)(64)(65)(66)(67). The severity of the ADPKD cystogenic mechanism(s) is likely to depend on modulation of the remaining non-mutant copy of PKD1/PKD2 potentially through de novo mutations, a stochastic event, altered functional role of polycystins and/or epigenetic inheritance that are actively under study.…”