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      Long-Term Ammonium Chloride or Sodium Bicarbonate Treatment in Two Models of Polycystic Kidney Disease

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          Administration of ammonium chloride aggravates, while short-term administration of sodium or potassium bicarbonate lessens the development of polycystic kidney disease in Han:SPRD rats. We have conducted studies to determine whether the protection afforded by the administration of sodium bicarbonate is sustained and prevents development of uremia during chronic administration and whether the effects of the administration of ammonium chloride and sodium bicarbonate are also observed in a different model of polycystic kidney disease, the CD1-pcy/pcy mouse. We found that chronic administration of 200 m M sodium bicarbonate to Han:SPRD rats inhibited cystic enlargement and prevented the subsequent development of interstitial inflammation, chronic fibrosis, and uremia. We also found that, while the administration of ammonium chloride has similar effects in Han:SPRD rats and CD1-pcy/pcy mice, the administration of sodium bicarbonate is only protective in the Han:SPRD rats. This probably reflects differences in these models (predominately involvement of proximal tubules in Han:SPRD rats and of collecting ducts and distal tubules in pcy/pcy mice) and the different location and nature of the renal metabolic responses to the administration of acid or alkaline load.

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          New insights into polycystic kidney disease and its treatment.

          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.

            Author and article information

            Nephron Exp Nephrol
            Cardiorenal Medicine
            S. Karger AG
            June 2001
            23 April 2001
            : 9
            : 3
            : 171-180
            aNephrology Research Unit and Division of Nephrology, Mayo Clinic, Rochester, Minn., and Departments of bMedicine and cAnatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kans., USA
            52609 Exp Nephrol 2001;9:171–180
            © 2001 S. Karger AG, Basel

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            Figures: 11, Tables: 2, References: 15, Pages: 10
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