Store-operated calcium entry mediated high glucose-induced podocyte injury and mitochondrial impairment




Tao, Yu
Chaudhari, Sarika
Yazdizadeh Shotorbani, Parisa
Ma, Rong


0000-0003-1128-3176 (Tao, Yu)

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Purpose: Diabetic Nephropathy (DN) is a major complication of diabetes mellitus, a metabolic disease initiated by high glucose (HG). Podocyte injury is associated with progression of DN. However, the mechanisms underlying podocyte injury induced by HG is poorly understood. Store-operated calcium entry (SOCE) is a multifunctional signaling pathway in many cell types. However, its role in podocyte injury in DN is not known. The aim of the present study was to determine if SOCE mediated HG-induced podocyte injury by impairing mitochondria. Methods: Immortalized human podocytes were used for all experiments. Western blot was conducted to evaluate protein abundance of Orai1 (the channel protein mediating SOCE) and nephrin (a podocyte specific protein). Calcium imaging was used to analyze SOCE. TMRE fluorescence was used to probe the mitochondria membrane potential (MMP).Results: HG (25mM) treatment for time periods ranging from 2 to 12 hours significantly increased Orai1 protein abundance. This HG effect was dose dependent. Consistently, Ca2+ imaging showed that HG (25 mM for 12 hours) significantly enhanced SOCE. Furthermore, the protein abundance of nephrin decreased in podocytes exposure to HG (25 mM), indicating podocyte injury by ambient HG. BTP2 (4 µM), a selective SOCE inhibitor blunted the HG-induced nephrin reduction. Moreover, HG (25 mM for 24 hours) decreased MMP, indicating mitochondria damage by HG. The MMP decrease was prevented by BTP2, suggesting the contribution of SOCE to the detrimental effect of HG.Conclusion: An upregulated SOCE contributes to HG-induced podocyte injury, possibly by impairing mitochondrial function.