Anti-inflammatory role of extracellular l-arginine through calcium sensing receptor in human renal proximal tubular epithelial (HK-2) cells

Authors

Samuel Shin, Calcium Signaling Laboratory, Research Service, Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC 20422, USA.
Eugenia Awuah Boadi, Calcium Signaling Laboratory, Research Service, Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC 20422, USA.
Saloni Shah, Calcium Signaling Laboratory, Research Service, Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC 20422, USA.
Madison Ezell, Calcium Signaling Laboratory, Research Service, Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC 20422, USA.
Peijun Li, Calcium Signaling Laboratory, Research Service, Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC 20422, USA.
Bidhan C. Bandyopadhyay, Calcium Signaling Laboratory, Research Service, Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC 20422, USA; Division of Renal Diseases & Hypertension, Department of Medicine, The George Washington University, Washington, DC 20037, USA; Department of Biomedical Engineering, The Catholic University of America, 620 Michigan Avenue NE, Washington, DC 20064, USA. Electronic address: bidhan.bandyopadhyay@va.gov.

Document Type

Journal Article

Publication Date

2-22-2023

Journal

International immunopharmacology

Volume

117

DOI

10.1016/j.intimp.2023.109853

Keywords

Ca(2+) signaling; Ca(2+)-sensing receptor; Inflammation; Nephroprotection; Oxidative stress; Proximal tubule; l-Arginine

Abstract

Renal tubular epithelial cells are capable of synthesizing interleukins (IL) in response to a variety of proinflammatory cytokines. Moreover, elevated urinary levels of IL have been shown in patients with various forms of nephritic diseases. However, the underlying intracellular signaling mechanism is unclear. Here we show the immunological signaling role of l-Arginine (l-Arg) through Ca-sensing receptor (CaSR) in human kidney 2 (HK-2) renal proximal tubular epithelial cells, using Ca imaging and patch clamp techniques and its mechanistic link to the downstream cellular function. Both pharmacological and siRNA inhibitors support the activation CaSR by extracellular l-Arg to induced Ca entry via a Transient receptor potential canonical (TRPC) channel in HK-2 cells mainly through the receptor operated Ca entry (ROCE). Activation of CaSR by l-Arg led to the rise in p-p38/p38 expression suggesting [Ca] as a regulator for p38-signaling pathways. Notably, l-Arg activated CaSR-induced Ca signaling reduced the expressions of key fibrotic, inflammatory, and apoptotic genes, suggesting its nephroprotective role via Ca signaling through CaSR in HK-2 cells. Since we found that the IL-6 expressions were inversely proportional to the increasing concentrations of l-Arg in HK-2 cells, we measured the release of IL-6, which steadily decreased as the concentrations of l-Arg were elevated. Taken together, extracellular l-Arg is a negative regulator for IL-6-induced inflammatory process, through the activation of CaSR and TRPC channel by ROCE pathway and can have a potential to alleviate inflammatory renal diseases.

APA Citation

Shin, Samuel; Awuah Boadi, Eugenia; Shah, Saloni; Ezell, Madison; Li, Peijun; and Bandyopadhyay, Bidhan C., "Anti-inflammatory role of extracellular l-arginine through calcium sensing receptor in human renal proximal tubular epithelial (HK-2) cells" (2023). GW Authored Works. Paper 2367.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/2367

Department

Medicine