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      Therapeutics in Renal Disease: The Road Ahead for Antiproliferative Targets

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          Discovery into the molecular basis of renal disease is occurring at an unprecedented rate. With the advent of the NIH Roadmap, there is a greater expectation of translating this knowledge into new treatments. Here, we review the therapeutic strategy to preserve renal function in proliferative renal diseases by directly inhibiting the mitogenic pathways within renal parenchymal cells that promote G₀ to G<sub>1</sub>/S cell-cycle phase progression. Reductionist methodologies have identified several antiproliferative molecular targets, and promising preclinical testing of leading small-molecule drugs to modulate these targets has now led to landmark clinical trials. Yet, this advancement into targeted therapy highlights important differences between the therapeutic goals of molecular nephrology versus molecular oncology and, by extension, the poorly understood role of alternative target activity in drug efficacy. Systems research to clarify these issues should accelerate the development of this promising therapeutic strategy.

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          Most cited references 66

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          Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist.

          The polycystic kidney diseases (PKDs) are a group of genetic disorders causing significant renal failure and death in children and adults. There are no effective treatments. Two childhood forms, autosomal recessive PKD (ARPKD) and nephronophthisis (NPH), are characterized by collecting-duct cysts. We used animal models orthologous to the human disorders to test whether a vasopressin V2 receptor (VPV2R) antagonist, OPC31260, would be effective against early or established disease. Adenosine-3',5'-cyclic monophosphate (cAMP) has a major role in cystogenesis, and the VPV2R is the major cAMP agonist in the collecting duct. OPC31260 administration lowered renal cAMP, inhibited disease development and either halted progression or caused regression of established disease. These results indicate that OPC31260 may be an effective treatment for these disorders and that clinical trials should be considered.
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            Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease.

            Autosomal dominant polycystic kidney disease (ADPKD) is a leading cause of end-stage renal disease. The vasopressin V2 receptor (VPV2R) antagonist OPC31260 has been effective in two animal models of PKD with pathologies that are probably related. Here we show, in a mouse model of ADPKD (Pkd2(-/tm1Som)), a similar cellular phenotype and response to OPC31260 treatment, with reduction of renal cyclic AMP (cAMP) levels, prevention of renal enlargement, marked inhibition of cystogenesis and protection of renal function.
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              Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease.

              Increased tubular epithelial cell proliferation is a prerequisite for cyst formation and expansion in polycystic kidney disease (PKD). Rapamycin is a potent antiproliferative agent. The aim of the present study was to determine the effect of rapamycin on tubular cell proliferation, cyst formation, and renal failure in the Han:SPRD rat model of PKD. Heterozygous (Cy/+) and littermate control (+/+) male rats were weaned at 3 wk of age and then treated with rapamycin 0.2 mg/kg per d intraperitoneally or vehicle (ethanol) for 5 wk. Vehicle-treated Cy/+ rats had a more than doubling of kidney size compared with +/+ rats. Rapamycin reduced the kidney enlargement by 65%. Rapamycin significantly reduced the cyst volume density in Cy/+ rats by >40%. Blood urea nitrogen was 59% increased in vehicle-treated Cy/+ rats compared with +/+ rats. Rapamycin reduced the blood urea nitrogen to normal in Cy/+ rats. The number of proliferating cell nuclear antigen (PCNA)-positive cells per noncystic tubule was eightfold increased in vehicle-treated Cy/+ compared with +/+ rats. Rapamycin significantly reduced the number of PCNA-positive cells in noncystic tubules of Cy/+ rats. In addition, the number of PCNA-positive cells per cyst in Cy/+ rats was significantly reduced by rapamycin. In summary, in a rat model of PKD, rapamycin treatment (1) decreases proliferation in cystic and noncystic tubules, (2) markedly inhibits renal enlargement and cystogenesis, and (3) prevents the loss of kidney function.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                April 2006
                09 December 2005
                : 103
                : 1
                : e6-e15
                aDivision of Nephrology, New York University School of Medicine, New York, N.Y., and bDivision of Nephrology, University of Washington Medical Center, Seattle, Wash., USA
                90138 PMC1440889 Nephron Exp Nephrol 2006;103:e6–e15
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 3, Tables: 2, References: 83, Pages: 1
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/90138


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