Therapies to slow polycystic kidney disease

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Advances in the understanding of cystogenesis and availability of animal models orthologous to human autosomal dominant polycystic kidney disease (ADPKD) and recessive polycystic kidney disease (ARPKD) will likely facilitate the development of treatments for these diseases. Proteins mutated in ADPKD and ARPKD, as well as in several animal models, are localized to renal primary cilia. These are thought to have a sensory function and contribute to the regulation of the intracellular calcium ([Ca2+]i). It seems likely that the maintenance of a differentiated renal epithelial phenotype, characterized by controlled fluid secretion and cell proliferation, requires precise functional coordination of cAMP and Ras/ Raf/MEK/ERK signaling by [Ca2+]i. [Ca2+]i alterations, linked to genetic defects causing polycystic kidney disease, may hinder negative feedback mechanisms that control cAMP and Ras/Raf/MEK/ERK signaling, and result in increased fluid secretion and cell proliferation. cAMP levels, Raf kinase activities and ERK phosphorylation are increased in polycystic kidneys. There is also evidence of abnormal cross-talk between cAMP and MAPK pathways, that can be reproduced in wild-type cells by altering [Ca2+]i. While cAMP inhibits Ras-Raf-1-stimulated phosphorylation of ERK in normal kidney cells, it markedly increases B-Raf kinase activity and ERK phosphorylation in polycystic kidney cells. Treatment strategies should probably be aimed at increasing [Ca2+]i, inhibiting Ras/Raf/MEK/ERK signaling or lowering cAMP in the distal nephron and collecting duct. Vasopressin is the major adenylyl cyclase agonist in the collecting duct principal cells via a V2 receptor. OPC31260, a V2 receptor antagonist, lowers renal cAMP and markedly inhibits cystogenesis in four animal models of polycystic kidney disease, three of which are orthologous to human diseases (PCK rat, ARPKD; pcy mouse, adolescent nephronophthisis; Pkd2WS25/- mouse, ADPKD). The renal selectivity and safety profile of this class of drugs make it an excellent candidate for clinical trials.

Original languageEnglish (US)
JournalNephron - Experimental Nephrology
Volume98
Issue number1
DOIs
StatePublished - 2004

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Polycystic Kidney Diseases
Autosomal Dominant Polycystic Kidney
Mitogen-Activated Protein Kinase Kinases
Kidney
Fluids and Secretions
Vasopressin Receptors
Animal Models
Phosphorylation
Therapeutics
Proto-Oncogene Proteins B-raf
raf Kinases
Cell Proliferation
Cilia
Nephrons
Vasopressins
Adenylyl Cyclases
Maintenance
Clinical Trials
Calcium
Phenotype

Keywords

  • Calcium
  • cAMP
  • Polycystic kidney disease
  • Raf
  • Ras
  • Vasopressin V2 receptor antagonists

ASJC Scopus subject areas

  • Nephrology

Cite this

Therapies to slow polycystic kidney disease. / Torres, Vicente.

In: Nephron - Experimental Nephrology, Vol. 98, No. 1, 2004.

Research output: Contribution to journalArticle

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