Vascular Complications of Polycystic Kidney Disease

Summary

Principal Investigator: Qi Qian
Affiliation: Mayo Clinic
Country: USA
Abstract: Dr. Qian's long-term objective is to contribute to a better understanding of kidney disease pathophysiology, especially the vascular complications of autosomal dominant polycystic kidney disease (ADPKD). Her aim, over five-years, is to become a well-trained independent physician scientist with advance theoretical and technical knowledge in genetics and molecular and cellular biology through the implementation of this proposal. The candidate's mentor, Dr. Torres, is an expert in clinical and vascular aspects of ADPKD and her co-mentor, Dr. Harris, brings a detailed knowledge of ADPKD genetics. The third mentor, Dr. Farrugia, is an expert in Ca2+ homeostasis and will provide valuable guidance for that part of the proposal. The particular focus of this proposal is to study the role of the ADPKD proteins, polycystin-1 and -2 in the vasculature and to determine if defects in these proteins are directly related to the vascular manifestations and hypertension associated with ADPKD. Preliminary studies have indicated that the polycystins are expressed in vascular smooth muscle cells (VSMC) and that they interact as a part of a polycystin complex that may play a role in maintaining intracellular Ca2+ The first two Specific Aims of the proposal are to examine the consequences of mutation to the murine Pkdl and Pkd2 genes, and over expression of the human protein in mouse, on the characteristics of VSMCs. These will be analyzed in vitro, as cultured VSMCs and in vivo, by study of the ultrastructure of the vasculature in the mouse mutants. Specific Aim 3 will identify components of a VSMC polycystin complex using imaging methods, co-immunoprecipitation and the yeast two- hybrid technique. The results of these studies will allow a VSMC polycystin complex to be defined and comparison made to corresponding complexes in epithelial cells. The final part of the proposal (Specific Aim 4) will examine the role of the polycystins in maintaining intracellular calcium homeostasis and analyze the consequences of Pkd1/2 mutation. Overall, the results from these studies should provide a clearer view of the function of the polycystins in VSMCs and the likely role that loss of these proteins may play in the vascular abnormalities and hypertension associated with ADPKD. This information will provide the basis for designing rational therapies for the treatment of these complications. This period of laboratory based study, plus the formalized career development program, is designed to train the candidate as a physician scientist with a unique expertise in vascular aspects of ADPKD.
Funding Period: 2003-06-01 - 2008-04-30
more information: NIH RePORT

Top Publications

  1. ncbi [Ca2+]i reduction increases cellular proliferation and apoptosis in vascular smooth muscle cells: relevance to the ADPKD phenotype
    Sertac N Kip
    Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minn 55905, USA
    Circ Res 96:873-80. 2005
  2. ncbi Pkd2+/- vascular smooth muscles develop exaggerated vasocontraction in response to phenylephrine stimulation
    Qi Qian
    Department of Medicine and Physiology, Eisenberg S 24, Nephrology, Mayo Clinic College of Medicine, 200 First Street, SW, Rochester, MN 55905, USA
    J Am Soc Nephrol 18:485-93. 2007
  3. ncbi Retinal arterial and venous occlusions in patients with ADPKD
    Qi Qian
    Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
    Nephrol Dial Transplant 22:1769-71. 2007
  4. ncbi Increased occurrence of pericardial effusion in patients with autosomal dominant polycystic kidney disease
    Qi Qian
    Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
    Clin J Am Soc Nephrol 2:1223-7. 2007
  5. ncbi Sirolimus reduces polycystic liver volume in ADPKD patients
    Qi Qian
    Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
    J Am Soc Nephrol 19:631-8. 2008
  6. ncbi Non-random distribution and sensory functions of primary cilia in vascular smooth muscle cells
    C J Lu
    Division of Nephrology and Hypertension, Mayo Clinic College of Medicine and Mayo Graduate School, Rochester, MN 55905, USA
    Kidney Blood Press Res 31:171-84. 2008
  7. ncbi Characterization of primary cilia in human airway smooth muscle cells
    Jun Wu
    Kidney Institute of the China People s Liberation Army, Changzheng Hospital, Second Military Medical University, Shanghai, People s Republic of China
    Chest 136:561-70. 2009
  8. ncbi Phenylephrine induces elevated RhoA activation and smooth muscle alpha-actin expression in Pkd2+/- vascular smooth muscle cells
    Hui Du
    Department of Medicine, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Mayo Graduate School, Rochester, MN 55905, USA
    Hypertens Res 33:37-42. 2010

Scientific Experts

  • Qi Qian
  • Hui Du
  • Jun Wu
  • Xiangling Wang
  • C J Lu
  • Gary C Sieck
  • Sertac N Kip
  • Changlin Mei
  • J Wu
  • H Du
  • G C Sieck
  • D A Jansen
  • N Xu
  • K L Jordan
  • Qun Ren
  • Stefan Somlo
  • Larry W Hunter
  • Vicente E Torres
  • Peter C Harris

Detail Information

Publications8

  1. ncbi [Ca2+]i reduction increases cellular proliferation and apoptosis in vascular smooth muscle cells: relevance to the ADPKD phenotype
    Sertac N Kip
    Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minn 55905, USA
    Circ Res 96:873-80. 2005
    ..This elevation can also be induced by reducing [Ca2+]i in wild-type VSMCs. The [Ca2+]i reduction and cAMP accumulation can cause an increase in both cellular proliferation and apoptosis, resembling Pkd mutant phenotype...
  2. ncbi Pkd2+/- vascular smooth muscles develop exaggerated vasocontraction in response to phenylephrine stimulation
    Qi Qian
    Department of Medicine and Physiology, Eisenberg S 24, Nephrology, Mayo Clinic College of Medicine, 200 First Street, SW, Rochester, MN 55905, USA
    J Am Soc Nephrol 18:485-93. 2007
    ..An enhanced Ca(2+)-independent force generation and elevated contractile protein expression likely contribute to these abnormalities...
  3. ncbi Retinal arterial and venous occlusions in patients with ADPKD
    Qi Qian
    Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
    Nephrol Dial Transplant 22:1769-71. 2007
  4. ncbi Increased occurrence of pericardial effusion in patients with autosomal dominant polycystic kidney disease
    Qi Qian
    Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
    Clin J Am Soc Nephrol 2:1223-7. 2007
    ..Autosomal dominant polycystic kidney disease (ADPKD) is a common hereditary disease with prominent connective tissue manifestations. A frequent occurrence of asymptomatic pericardial effusion has been observed in patients with ADPKD...
  5. ncbi Sirolimus reduces polycystic liver volume in ADPKD patients
    Qi Qian
    Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
    J Am Soc Nephrol 19:631-8. 2008
    ..In summary, treatment with sirolimus was associated with decreased polycystic liver volume, perhaps by preventing aberrant activation of mTOR in epithelial cells lining the cysts...
  6. ncbi Non-random distribution and sensory functions of primary cilia in vascular smooth muscle cells
    C J Lu
    Division of Nephrology and Hypertension, Mayo Clinic College of Medicine and Mayo Graduate School, Rochester, MN 55905, USA
    Kidney Blood Press Res 31:171-84. 2008
    ..These observations suggest a role for primary cilia in mechanochemical sensing in vasculature...
  7. ncbi Characterization of primary cilia in human airway smooth muscle cells
    Jun Wu
    Kidney Institute of the China People s Liberation Army, Changzheng Hospital, Second Military Medical University, Shanghai, People s Republic of China
    Chest 136:561-70. 2009
    ..However, cilia-related research has been limited to a few cell and tissue types; to our knowledge, no literature exists on primary cilia in airway smooth muscle (ASM). The aim of this study was to characterize primary cilia in human ASM...
  8. ncbi Phenylephrine induces elevated RhoA activation and smooth muscle alpha-actin expression in Pkd2+/- vascular smooth muscle cells
    Hui Du
    Department of Medicine, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Mayo Graduate School, Rochester, MN 55905, USA
    Hypertens Res 33:37-42. 2010
    ..These defects could potentially contribute to the genesis of vascular complications in ADPKD, thus providing new areas for further research and therapeutic targeting...