New insights into polycystic kidney disease and its treatment

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Abstract

Major advances in the understanding of the genetics and pathogenesis of autosomal dominant polycystic kidney disease have occurred within the past year. The proteins encoded by the PKD1 and PKD2 genes, polycystin 1 and polycystin 2, are membrane proteins, capable of interacting physically in vitro, and are likely components of a complex signalling pathway. The majority of PKD1 and PKD2 mutations so far identified are unique inactivating mutations dispersed over the entire genes. Immunohistochemical studies have shown that polycystin 1 and polycystin 2 are developmentally regulated and are overexpressed in polycystic kidneys. The cysts probably result from clonal expansions of single cells. The demonstration of loss of heterozygosity for PKD1 and the absence of immunoreactive polycystin 1 in approximately 20% of the cysts supports a two-hit tumor suppressor gene model of cystogenesis. Regardless of the nature of the initial pathogenic mechanism, the cysts in autosomal dominant polycystic kidney disease are accompanied by partial dedifferentiation of the epithelial cells, disregulation of epithelial cell proliferation, expression of a secretory phenotype, and disarray of cell matrix interactions which leads to interstitial inflammation and matrix accumulation. Recent observations in animal models of inherited polycystic kidney disease have implicated oxidative stress in its pathogenesis. These downstream pathogenetic events have been targeted for intervention, and an increasing number of studies have demonstrated that the course of polycystic kidney disease in rodents can be altered by environmental and pharmacological interventions. Nevertheless, these experimental observations cannot be extrapolated to human autosomal dominant polycystic kidney disease. The recent generation of mice with PKD1 or PKD2 targeted mutations will help to bridge this gap.

Original languageEnglish (US)
Pages (from-to)159-169
Number of pages11
JournalCurrent Opinion in Nephrology and Hypertension
Volume7
Issue number2
DOIs
StatePublished - 1998

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Polycystic Kidney Diseases
Autosomal Dominant Polycystic Kidney
Cysts
Mutation
Epithelial Cells
Loss of Heterozygosity
Tumor Suppressor Genes
Cell Communication
Genes
Rodentia
Membrane Proteins
Oxidative Stress
Animal Models
Cell Proliferation
Pharmacology
Inflammation
Phenotype
polycystic kidney disease 1 protein
polycystic kidney disease 2 protein

ASJC Scopus subject areas

  • Nephrology
  • Internal Medicine

Cite this

New insights into polycystic kidney disease and its treatment. / Torres, Vicente.

In: Current Opinion in Nephrology and Hypertension, Vol. 7, No. 2, 1998, p. 159-169.

Research output: Contribution to journalArticle

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