An Approach to Evaluate Inhibition of Cyclophilin D-Sensitive Mitochondrial Permeability Transition Pore Formation in Chronic Kidney Disease
Roach, Allie M.
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CitationRoach, Allie M. 2018. An Approach to Evaluate Inhibition of Cyclophilin D-Sensitive Mitochondrial Permeability Transition Pore Formation in Chronic Kidney Disease. Master's thesis, Harvard Extension School.
AbstractThe mitochondrial permeability transition pore (mPTP) contributes to pathological outcomes in various contexts of tissue injury and disease involving mitochondrial perturbation, including in the kidneys. The prominent stressors leading to formation of the mPTP include increased cellular calcium influx and increased reactive oxygen species (ROS) production or accumulation. Subsequent opening of the mPTP can be a key contributor to poor outcome through several possible mechanisms including a decreased ability of cells to produce ATP and the induction of necrotic and apoptotic cell death. Here, we prevented expression of a critical modulator of the mPTP, namely Cyclophilin D (CypD), in mice that develop chronic kidney disease (CKD) by crossing mice with CypD deficiency to those carrying the Col4a3-/- mutation modeling Alport nephropathy. The mouse model of Alport nephropathy exhibits increased ROS production and tubule epithelium cell death in the kidney, suggesting that mPTP opening may be occurring and driving disease progression. In the present study, we found that human and murine kidneys with CKD exhibited alterations indicative of mitochondrial dysfunction possibly associated with mPTP formation. CypD deletion, however, did not improve survival or renal function in Alport mice nor did it reduce histopathology. Together, these results demonstrate that inhibition of CypD activity as an approach to limit mPTP formation does not appear to be a viable pharmacologic target for the treatment of Alport nephropathy.
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