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*
Nephrology Research Unit, Division of Nephrology and Internal Medicine,
Mayo Clinic and Mayo Foundation, Rochester, Minnesota
Renal Biopsy Laboratory, Mayo Clinic and Mayo Foundation, Rochester,
Minnesota
§
Department of Pediatrics, Mayo Clinic and Mayo Foundation, Rochester,
Minnesota
Section of Nephrology, Department of Internal Medicine, Yale School of
Medicine, New Haven, Connecticut.
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Section of Nephrology, Department of Genetics, Yale School of Medicine,
New Haven, Connecticut.
Correspondence to Dr. Vicente E. Torres, Department of Nephrology, Mayo Clinic, Plummer 549, 200 First Street SW, Rochester, MN 55905. Phone: 507-284-3588; Fax: 507-284-8286; E-mail: torres.vicente{at}mayo.edu
Abstract. The expression of polycystin-1 in the vascular smooth muscle cells (VSMC) of elastic and large distributive arteries suggests that some vascular manifestations of autosomal-dominant polycystic kidney disease (ADPKD) result directly from the genetic defect. Intracranial aneurysms have been reported in PKD2, as well as in PKD1 families. To determine whether the vascular expression of polycystin-2 is similar to that of polycystin-1, the expression of PKD2 mRNA and protein in cultured pig aortic VSMC was studied and immunofluorescence and immunohistochemistry were used to study the localization of polycystin-2 in cultured pig aortic VSMC, pig ascending thoracic aorta, and normal elastic and intracranial arteries and intracranial aneurysms obtained at autopsy from patients without or with ADPKD. Tissues derived from Pkd2 wild-type and Pkd2 null mice were used to confirm the specificity of the immunostaining for polycystin-2. Northern blots of VSMC revealed the expected 5.3-kb band. Western blotting detected a 110-kb band in a 100,000 x g fraction of VSMC homogenates. Cultured VSMC as well as VSMC between the elastic lamellae of pig thoracic aorta were positive for polycystin-2 by immunofluorescence. The staining pattern was cytoplasmic. Treatment of the cells before fixation with Taxol, colchicine, or cytochalasin-D altered the pattern of staining in a way suggesting alignment with the cytoskeleton. The immunohistochemical staining for polycystin-2 was abolished by extraction with 0.5% Triton X-100, indicating that polycystin-2 is not associated with the cytoskeleton. Weak immunoreactivity for polycystin-2, which was markedly enhanced by protease digestion, was detected in formaldehydefixed normal human elastic and intracranial arteries. Immunostaining of variable intensity for polycystin-2, which was not consistently enhanced by protease digestion, was seen in the spindle-shaped cells of the wall of the intracranial aneurysms. The similar expression of polycystin-1 and polycystin-2 in the vascular smooth muscle is consistent with the proposed interaction of these proteins in a single pathway. These observations suggest a direct pathogenic role for PKD1 and PKD2 mutations in the vascular complications of ADPKD.
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