l-ornithine activates Ca2+ signaling to exert its protective function on human proximal tubular cells, 2019, Shin et al

Andy · Nov 28, 2019

Oxidative stress and reactive oxygen species (ROS) generation can be influenced by G-protein coupled receptor (GPCR)-mediated regulation of intracellular Ca2+ ([Ca2+]i) signaling. ROS production are much higher in proximal tubular (PT) cells; in addition, the lack of antioxidants enhances the vulnerability to oxidative damage.

Despite such predispositions, PT cells show resiliency, and therefore must possess some inherent mechanism to protect from oxidative damage. While the mechanism in unknown, we tested the effect of l-ornithine, since it is abundantly present in PT luminal fluid and can activate calcium-sensing receptor (CaSR), a GPCR, expressed in the PT luminal membrane.

We used human kidney 2 (HK−2) cells, a PT cells line, and performed Ca2+ imaging and electrophysiological experiments to show that l-ornithine has a concentration-dependent effect on CaSR activation. We further demonstrate that the operation of CaSR activated Ca2+ signaling in HK-2 cells mediated by the transient receptor potential canonical (TRPC) dependent receptor-operated Ca2+ entry (ROCE) using pharmacological and siRNA inhibitors.

Since PT cells are vulnerable to ROS, we simulated such deleterious effects using genetically encoded peroxide-induced ROS production (HypeRed indicator) to show that the l-ornithine-induced ROCE mediated [Ca2+]i signaling protects from ROS production. Furthermore, we performed cell viability, necrosis and apoptosis assays, and mitochondrial oxidative gene expression to establish that presence of l-ornithine rescued the ROS-induced damage in HK-2 cells. Moreover, l-ornithine-activation of CaSR can reverse ROS production and apoptosis via mitogen-activated protein kinase p38 activation.

Such nephroprotective role of l-ornithine can be useful as the translational option for reversing kidney diseases involving PT cell damage due to oxidative stress or crystal nephropathies.
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Paywall, https://www.sciencedirect.com/science/article/abs/pii/S0898656819302803
Scihub, https://sci-hub.se/10.1016/j.cellsig.2019.109484

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l-ornithine activates Ca2+ signaling to exert its protective function on human proximal tubular cells, 2019, Shin et al

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l-ornithine activates Ca2+ signaling to exert its protective function on human proximal tubular cells, 2019, Shin et al

Andy Committee Member

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