Human Uremic Persistent Hyperparathyroidism: Functional and Molecular Aspects

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DESCRIPTION (provided by applicant): Patients receiving dialysis for end stage kidney failure often develop overactivity of their parathyroid glands, which can persist long after successful kidney transplantation and contributes to adverse graft and recipient outcomes. Causes of the abnormal, poorly suppressible parathyroid function after transplantation have been little studied and are incompletely understood. Patients with post-transplant, persistent secondary hyperparathyroidism (PSHPT) would be expected to show alterations in parathyroid cell (PTC) function due to changes in protein/gene expression and/or function influencing proliferation, PTH gene expression and set-point of secretion. Transplant recipients with autosomal dominant polycystic kidney disease (ADPKD) are at higher risk for post transplant parathyroidectomy. The identification of polycystins (PC) in PTC's, and their function as plasma membrane calcium sensors/channels have been well described. PC's also utilize intracellular signaling pathways similar to those of the calcium-sensing receptor (CaR). These observations support the hypothesis that PCL's play a role in parathyroid function. Elucidating the molecular basis of PSHPT and the role of PCL's in PTC function will assist in developing therapies and strategies that could optimize patient and graft outcomes. These issues will be addressed by undertaking the following specific aims: Aim 1: Elucidate the characteristics of persistent hypersecretion and proliferation characteristic of PSHPT in renal transplant patients relative to dialysis patients, by quantifying the parathyroid secretory and proliferative responses in vitro to changes in the extracellular calcium concentration (Ca2+) and 1,25 (OH)2 vitamin D3. Aim 2: Investigate the key qualitative and quantitative differences between parathyroid glands of transplant and dialysis patients with or without ADPKD and PSHPT with regard to CaR-regulated signaling pathways that have been implicated in the abnormal Ca2+-regulated PTH release in primary HPT and dialysis patients. Specific Aim 3: Determine the relationship between abnormal Ca2+-regulated processes and the expression of key genes implicated in the control of parathyroid function in PTC's of dialysis and transplant patients with and without PKD. If these genes are over- or underexpressed, we will assess the effect of correcting their expression using adeno-associated viral vectors or RNA silencing. Specific Aim 4: Identify novel genes contributing to PSHPT using DNA microarrays.