Abstract
Loss of podocytes is a hallmark of diabetic nephropathy, and a growing body of evidence indicates that podocytes are susceptible to palmitic acid (PA). We have previously shown that AS-IV inhibited PA-induced podocyte apoptosis by activating sarcoendoplasmic reticulum Ca2+ ATPase (SERCA), which indicate calcium regulation may involve in the process. Immunofluorescence staining, Western blot and flow cytometry were used to measure the protective efficacy of AS-IV to ameliorate PA-induced ER stress and podocyte apoptosis. Meanwhile, AS-IV inhibited cytochrome c release, decreased mitochondrial membrane potential, accompany with the depletion of endoplasmic reticulum Ca2+ and elevation of cytosolic and mitochondrial Ca2+. Sequestration of cytosolic calcium with BAPTA-AM limited the response of podocyte apoptosis, while during the process the effect of AS-IV was also restrained. In contrast, elevation of cytosolic calcium with calcium ionophore ionomycin was depressed by AS-IV addition. Furthermore, inhibiting TRPC6 expression with SKF96365 or TRPC6 siRNA counteracted the beneficial effect of AS-IV. Our study provides further evidence to conclude the inhibitory effect of AS-IV to podocyte apoptosis is Ca2+-dependent. And the efficacy correlates with inhibiting TRPC6-mediated Ca2+ influx, and then cellular Ca2+ disturbance was coordinated.
Highlights
Podocytes are terminally differentiated epithelial cells in the filtration barrier of the kidney
Our previous investigation showed that Astragaloside IV (AS-IV) treatment could ameliorate podocyte injury via sarcoendoplasmic reticulum Ca2+ ATPase 2 (SERCA2)-dependent ER stress reduction, which indicates that Ca2+ may take part in the regulatory role of AS-IV on podocyte apoptosis [13, 14]
To evaluate the anti-apoptosis activity of AS-IV, podocytes were exposed to palmitic acid (PA) and AS-IV at the indicated concentrations
Summary
Podocytes are terminally differentiated epithelial cells in the filtration barrier of the kidney. The class C transient receptor potential (TRPC) channels are C a2+-permeable cation channels expressed in the plasma membrane of a large amount of tissue and cell type including kidney [6]. Astragaloside IV (AS-IV) is a representative saponin isolated from Astragalus membranaceus (Fisch) Bge, which possesses various pharmacological activities such as inhibiting fibrosis, oxidative stress and apoptosis in kidney disease [10,11,12]. Our previous investigation showed that AS-IV treatment could ameliorate podocyte injury via sarcoendoplasmic reticulum Ca2+ ATPase 2 (SERCA2)-dependent ER stress reduction, which indicates that Ca2+ may take part in the regulatory role of AS-IV on podocyte apoptosis [13, 14]. We further showed that Ca2+ homeostasis was disrupted with the administration of palmitic acid (PA), accompanied with the ascending cytochrome c release and mitochondrial membrane potential. The efficacy of AS-IV linking with PA-induced ER stress and apoptosis in mouse podocyte was determined, and the mechanism relative to TRPC6 was been investigated
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