Browsing by Subject "fluid-filled cysts"

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    Effects of Lysophosphatidic Acid (LPA) and Antidiuretic Hormone (ADH) on Cl- Secretory Responses in Polycystic Kidney Disease (PKD)
    (Office of the Vice Chancellor for Research, 2013-04-05) Martinez, Gabriel M.; Flaig, Stephanie; Blazer-Yost, Bonnie L.
    Polycystic kidney disease (PKD) is a genetic disease that causes the formation of fluid-filled cysts in the kidney and other organs such as the liver and pancreas. Kidney function is seemingly unaltered despite substantial cyst development over the first four to six decades of life, but then the decline in renal function is precipitous often leading to complete renal failure in 5 years. Antidiuretic hormone (ADH) causes an increase in Cl- secretion into the cyst lumen, and one of the drugs in human clinical trials for treatment of PKD is an ADH receptor antagonist. The hormone works by stimulating cAMP production, which leads to the Cl- secretion. Interestingly, we have found that cyst fluid from human patients also causes a secretory Cl- flux that can lead to the growth of the remaining intact cysts. The active component of the cyst fluid is LPA, a phospholipid that acts as an extracellular signaling molecule. This secretion is important in late stage disease when large cysts are likely to leak or burst contributing to the rapid decline in renal function. Electrophysiological techniques were implemented to compare the ion fluxes stimulated by ADH and LPA. In the mpkCCDc14 (mouse principal cells of the cortical collecting duct clone 4) cell line we found that the Cl- secretory pathways stimulated by the two factors are separate and independent. Further indication of this separation is our finding that LPA stimulation does not increase cAMP levels. Therefore we have identified an additional target for potential pharmaceutical intervention in the treatment of PKD.
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    Pioglitazone, an Insulin Sensitizing Drug, Attenuates the Development of Kidney and Liver Disease in the PCK Rodent Model of Polycystic Kidney Disease
    (Office of the Vice Chancellor for Research, 2010-04-09) Blazer-Yost, Bonnie L.; Haydon, Julie; Eggelston, Tracy; Chen, Jey-Hsin; Torres, Vicente E.; Gattone, Vincent
    Polycystic kidney disease is a genetic disorder characterized by growth of fluid-filled cysts predominately in kidney and liver. The only treatment currently available is the removal/aspiration of the largest cysts or organ transplantation. Promising pharmaceutical agents in clinical trials interfere with the action of hormones that increase cAMP thereby inhibiting secretion of Cl-, and compensatory fluid flux, into the cysts. Other treatments proposed include chemotherapeutic and immunosuppressive drugs that interfere with cellular proliferation as well as with signaling pathways for Cl- secretion. Long-term use of these agents will have multiple side effects. Based on a recent observation that peroxisome proliferator activated receptor γ agonists such as Actos (pioglitazone) and Avandia (rosiglitazone) decrease mRNA levels of a Cl- transport protein and the Cl- secretory response to vasopressin stimulation in cultured renal cells, it is hypothesized that PPARγ agonists will inhibit cyst growth. The current studies show that a 7 or 14 week feeding regimen of 20 mg/Kg BW pioglitazone inhibits renal and hepatic bile duct cyst growth in a rodent model orthologous to human PKD. In addition, the degree of renal cortical fibrosis was diminished in the pioglitazone-treated animals after 14 weeks. These results suggest that PPARγ agonists may be effective in controlling both renal and hepatic cyst growth and renal fibrotic development in polycystic kidney disease.
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    Renal Cyst Fluid From Human Polycystic Kidney Disease Patients Stimulates Cl- Transport: Active Factor and Cl- Channels
    (Office of the Vice Chancellor for Research, 2011-04-08) Blazer-Yost, Bonnie L.; Blacklock, Brenda; Bacallao, Robert L.; Gattone, Vincent H.
    Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the slow growth of fluid-filled cysts predominately in the kidney and in liver bile ducts. The factors involved in modifying the rate of cyst growth through epithelial proliferation or secretion are critical to understanding the progression of the disease. In addition, elucidation of mechanisms that potentiate the normal progression to renal failure will provide the basis for therapeutic intervention. Of note are the observations that the decline in renal function in middle age is precipitous and that renal injury results in an exacerbation of cyst growth. Using electrophysiological and biochemical techniques, we identified LPA (lysophosphatic acid) as a component of cyst fluid that stimulates secretory Cl- transport via two anion channels, CFTR and TMEM16a, in the mpkCCDcl4 model of renal principal cells. The LPA effect is manifested through receptors located on the basolateral membrane of polarized renal cells resulting in stimulation of channel activity in the apical membrane. Concentrations of LPA measured in ADPKD cyst fluid and in normal serum are sufficient to maximally stimulate ion transport. Thus, cyst fluid seepage into the interstitial space and/or leakage of vascular LPA are capable of stimulating epithelial cell secretion resulting in cyst enlargement. Research Support: IUPUI Membrane Biosciences Signature Center Grant