Location

Rochester, Minnesota Clinical Profile

Summary

My research centers on the study of polycystic kidney (PKD) and liver (PLD) diseases, and related disorders. The focus has ranged from identification of genes mutated in these diseases and study of expression and function of encoded proteins encoded to epidemiology, phenotypic characterization, and preclinical and clinical therapeutic trials. Current work in my laboratory examines the hypothesis that upregulation of cyclic nucleotide signaling caused by dysregulation of intracellular calcium homeostasis has a central role in the pathogenesis of PKD. We have found that cAMP levels are consistently increased in polycystic kidneys, that phosphodiesterase 1 (PDE1), PDE3 and PDE4 activities and/or protein levels are reduced in murine cystic compared to wild-type kidneys. Alterations in cyclic nucleotide catabolism may render the cystic epithelium particularly susceptible to factors acting on Gs coupled receptors, accounting at least in part for upregulation of cyclic nucleotide signaling in PKD and contributing to its progression. These observations provide a rationale for therapeutic strategies targeting cyclic nucleotide metabolism in a tissue selective manner thus limiting toxicity. In collaboration with Dr. Vincent Gattone from the University of Indiana, we found that vasopressin V2 receptor antagonists lower cAMP levels in the renal tubules mainly involved in cystogenesis and inhibit progression of PKD in animal models orthologous to autosomal recessive PKD (PCK rat), nephronophthisis (pcy mouse) and autosomal dominant PKD (Pkd2-/WS25 mice). We confirmed that this protective effect is due to V2 receptor antagonism by generating PCK rats that lack circulating AVP and treating them with the AVP V2 agonist 1-deamino-8-D-arginine AVP (DDAVP). In collaboration with Dr. Larusso’s laboratory at Mayo, we also found that octreotide also reduces tissue levels of cAMP and protects not only the kidney, but also the liver. Our goal is to advance potential therapies for PKD from bench to the bedside. Clinical research and trials towards this goal are funded by:
  • The National Institutes of Health (Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease, CRISP, ClinicalTrials.gov, NCT01039987
  • Polycystic Kidney Disease Treatment Network, HALT-PKD Clinical Trials, ClinicalTrials.gov, NCT00283686)
  • The PKD Foundation (Clinical Path Institute PKD consortium)
  • Industry (Tolvaptan Efficacy and Safety in Management of ADPKD and its Outcomes Phase 2/4, ClinicalTrials.gov, NCT00413777
  • Tolvaptan Efficacy and Safety in Management of ADPKD and its Outcomes Phase 3/4, ClinicalTrials.gov, NCT00428948
  • Long-term Efficacy and Safety of Oral Tolvaptan Tablet Regimens in Subjects with ADPKD, ClinicalTrials.gov, NCT01214421
  • Octreotide for severe Polycystic Liver Disease, ClinicalTrials.gov, NCT00426153

Recent Publications

See my publications

Professional Details

Primary Appointment

  1. Nephrology

Administrative Appointment

  1. Nephrology

Academic Rank

  1. Professor of Medicine

Education

  1. Resident - Nephrology Mayo Graduate School of Medicine, Mayo Clinic College of Medicine
  2. Resident - Internal Medicine Mayo Graduate School of Medicine, Mayo Clinic College of Medicine
  3. Internship - Straight Medical Internship Mount Sinai Medical Center
  4. Fellow - Research Fellow, Division of Nephrology Mayo Graduate School of Medicine, Mayo Clinic College of Medicine
  5. Fellow - Research Fellow, Division of Nephrology Hospital Clinico y Provincial de Barcelona Faculty of Medicine
  6. PhD Universidad de Barcelona
  7. Internship Hospital Clinico y Provincial de Barcelona Faculty of Medicine
  8. MD Universidad de Barcelona
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BIO-00077282

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