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The genes and proteins associated with poly-cystic kidney diseases
1Department of Medicine, Mount Sinai School of Medicine, Box 1243, 1425 Madison Avenue, New York, NY 10029, USA.
Insights
Polycystin proteins, encoded by PKD1 and PKD2 genes, regulate kidney tubule development in autosomal dominant polycystic kidney disease (ADPKD). Aberrant signaling in ADPKD disrupts normal kidney morphogenesis.
Area of Science:
- Nephrology
- Molecular Biology
- Genetics
Background:
- Polycystic kidney diseases (PKDs) are genetically heterogeneous, including autosomal dominant (ADPKD), autosomal recessive (ARPKD), nephronophthisis, and medullary cystic disease.
- The PKD1 and PKD2 genes, encoding polycystin-1 and polycystin-2, are central to ADPKD pathogenesis.
- Fibrocystin (PKHD) and nephrocystin (NPH1) are implicated in ARPKD and nephronophthisis, respectively, suggesting shared cellular pathways.
Purpose of the Study:
- To investigate the function of polycystin complexes in renal tubule development.
- To elucidate the molecular mechanisms underlying ADPKD pathogenesis.
- To explore potential similarities in cellular pathways affected by different genetic PKD forms.
Main Methods:
- Structure-function analysis of polycystin proteins.
- Investigation of protein-protein interactions within polycystin complexes.
- Analysis of gene expression patterns in ADPKD epithelia.
Main Results:
- Polycystins appear to form multiprotein complexes involved in cell adhesion and signaling.
- These complexes regulate gene transcription controlling cell proliferation and differentiation.
- ADPKD epithelia exhibit altered collagen adhesion, reduced migration, and aberrant fetal gene expression.
Conclusions:
- The polycystin complex acts as a critical regulator of renal tubule morphogenesis.
- Dysfunctional polycystin complexes contribute to the aberrant development seen in ADPKD.
- Further research into fibrocystin and nephrocystin may reveal conserved roles in PKD development.
Abstract:
Genetically based polycystic kidney diseases include autosomal dominant (ADPKD) and recessive (ARPKD) polycystic kidney diseases, nephronophthisis and medullary cystic disease. The PKD1 and PKD2 genes responsible for ADPKD and their respective encoded proteins polycystin-1 and polycystin-2 are under intense study and clues are developing as to their function and roles in the disease process. Structure-function analysis suggests that polycystins form multiprotein complexes with focal adhesion and cell-cell adherens junction proteins, which then initiate intracellular signaling events culminating in regulation of transcription of genes controlling proliferation and differentiation. Although less is known about the PKHD-encoded fibrocystin responsible for ARPKD or about the NPH1-encoded nephrocystin responsible for nephronophthisis, it is proposed that they function in the same cellular pathway involving protein-protein interactions, signal transduction and regulation of gene transcription. ADPKD epithelia are more adherent to collagen, less migratory, fail to recruit FAK to polycystin complexes and show aberrant, persistent expression of the fetal genes Erb-B2 and beta2 subunit of NaK-ATPase after birth. It is suggested that the function of the polycystin complex is to act as a key developmental regulator of renal tubule morphogenesis.