Urotensin II-induced store-operated Ca2+ entry contributes to glomerular mesangial cell proliferation and extracellular matrix protein production under high glucose conditions

Hitesh Soni,Adebowale Adebiyi

doi:10.1038/s41598-017-18143-x

Hitesh Soni, Adebowale Adebiyi

Open Access

https://doi.org/10.1038/s41598-017-18143-x

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Abstract

Glomerular mesangial cell (GMC) proliferation and matrix expansion are pathological hallmarks of a wide range of kidney diseases, including diabetic nephropathy. Although the circulating level of peptide hormone urotensin II (UII) and kidney tissue expression of UII and UII receptors (UTR) are increased in diabetic nephropathy, it remains unclear whether UII regulates GMC growth and extracellular matrix (ECM) accumulation. In this study, we tested the hypothesis that UII-induced Ca2+ signaling controls GMC proliferation and ECM production under normal and high glucose conditions. Mouse GMCs cultured under normal glucose conditions proliferated and synthesized ECM proteins in response to stimulation by mouse UII. UII-induced GMC proliferation and ECM protein synthesis were dependent on TRPC4 channel-mediated store-operated Ca2+ entry (SOCE) and sequential activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and Ca2+/cAMP response element-binding protein (CREB) transcription factor. Under high glucose conditions, GMCs synthesized UII. Moreover, proliferation and ECM production in high glucose-challenged GMCs were attenuated by selective UTR antagonist, TRPC4 channel blocker, and CaMKII and CREB-binding protein/p300 inhibitors. These findings indicate that UII-induced SOCE via TRPC4 channels stimulates CaMKII/CREB-dependent GMC proliferation and ECM protein production. Our data also suggest that UII synthesis contributes to GMC proliferation and ECM accumulation under high glucose conditions.

Highlights

Experimental data from a variety of animal models suggest that peptide hormone urotensin II (UII) regulates renal functions, including vascular bed perfusion, glomerular filtration, and electrolyte homeostasis[1,2,3]
Studies have shown that renal UII production may be associated with diabetic nephropathy[1,4,5,7], little is known about the function of UII in renal glomerulus in health and disease
The findings presented in this study are the first indication that UII-induced [Ca2+]i elevation stimulates Glomerular mesangial cell (GMC) proliferation and extracellular matrix (ECM) protein production

Summary

Introduction

Experimental data from a variety of animal models suggest that peptide hormone urotensin II (UII) regulates renal functions, including vascular bed perfusion, glomerular filtration, and electrolyte homeostasis[1,2,3]. Exposure of cultured glomerular mesangial cell (GMCs) to high glucose concentrations induces proliferation, ECM protein synthesis, and hypertrophy, thereby mimicking the effect of hyperglycemia in diabetic nephropathy[10,11]. TRPC channels, comprising of seven members (TRPC17) function as Ca2+ release channels in excitable and non-excitable cells[18] These channels contribute to Ca2+ signaling in GMCs, including store-operated Ca2+ entry (SOCE)[19]. It is unclear whether SOCE elicited by UII involves TRPC4 channels and controls GMC growth Given that both UII production and mesangial expansion are associated with diabetic nephropathy[4,7,9,10], we tested the hypothesis that UII-induced SOCE via TRPC4 channels modulates mouse GMC growth and ECM protein accumulation under normal and high glucose conditions

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