Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by uncontrollable epithelial cell growth, cyst formation, and kidney malfunction. In the present study, we investigated the antiproliferative effects of the treatment with the combination of paclitaxel (PAC) and all-trans retinoic acid (ATRA) on ADPKD epithelial cells. Our results show that the combined treatment with 1 nM PAC and 10 nM ATRA significantly suppressed ADPKD cell proliferation (20%), while the treatment with ATRA or PAC alone had no such effect. Treatment with PAC and ATRA induced cell cycle arrest at the G2/M phase and apoptosis by upregulating p53 and caspase-8 expression and increased the intracellular calcium (Ca2+) level possibly by enhancing Ca2+ uptake via plasma membrane channels. In addition, this treatment suppressed extracellular signal-regulated kinase signaling possibly through mitogen-activated protein kinase phosphatase-1 activation. Thus, the combination of PAC and ATRA can be explored as a potential treatment regimen for ADPKD.
Highlights
Polycystic kidney disease (PKD) is a life-threatening inherited monogenic disorder characterized by the progressive decline in the kidney function resulting from the renal cysts owing to enhanced cell proliferation [1, 2]
By interacting with the integral membrane PC-2, which is encoded by PKD2, the PC-1/2 complex produces cation-permeable currents that are involved in the modulation of the intracellular calcium (Ca2+) uptake or cell division [4]
Dysfunction of PC-1/2 may lead to alternative Ca2+ homeostasis to activate cyclic adenosine monophosphate and triggers uncontrollable cell proliferation, which initiates cyst formation in autosomal dominant PKD (ADPKD) [4]
Summary
Polycystic kidney disease (PKD) is a life-threatening inherited monogenic disorder characterized by the progressive decline in the kidney function resulting from the renal cysts owing to enhanced cell proliferation [1, 2]. ADPKD has a much higher frequency (1 : 400 to 1 : 1,000) than ARPKD [1]. ADPKD can be caused by mutations in either one of the two genes, PKD1 in 85% cases or PKD2 in 15% cases [3,4,5]. The PKD1 gene encodes polycystin-1 (PC-1) located in the plasma membrane. By interacting with the integral membrane PC-2, which is encoded by PKD2, the PC-1/2 complex produces cation-permeable currents that are involved in the modulation of the intracellular calcium (Ca2+) uptake or cell division [4]. Dysfunction of PC-1/2 may lead to alternative Ca2+ homeostasis to activate cyclic adenosine monophosphate (cAMP) and triggers uncontrollable cell proliferation, which initiates cyst formation in ADPKD [4]
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