Store-operated calcium entry: Pivotal roles in renal physiology and pathophysiology

Abstract

Research conducted over the last two decades has dramatically advanced the understanding of store-operated calcium channels (SOCC) and their impact on renal function. Kidneys contain many types of cells, including those specialized for glomerular filtration (fenestrated capillary endothelium, podocytes), water and solute transport (tubular epithelium), and regulation of glomerular filtration and renal blood flow (vascular smooth muscle cells, mesangial cells). The highly integrated function of these myriad cells effects renal control of blood pressure, extracellular fluid volume and osmolality, electrolyte balance, and acid-base homeostasis. Many of these cells are regulated by Ca²⁺ signaling. Recent evidence demonstrates that SOCCs are major Ca²⁺ entry portals in several renal cell types. SOCC is activated by depletion of Ca²⁺ stores in the sarco/endoplasmic reticulum, which communicates with plasma membrane SOCC via the Ca²⁺ sensor Stromal Interaction Molecule 1 (STIM1). Orai1 is recognized as the main pore-forming subunit of SOCC in the plasma membrane. Orai proteins alone can form highly Ca²⁺ selective SOCC channels. Also, members of the Transient Receptor Potential Canonical (TRPC) channel family are proposed to form heteromeric complexes with Orai1 subunits, forming SOCC with low Ca²⁺ selectivity. Recently, Ca²⁺ entry through SOCC, known as store-operated Ca²⁺ entry (SOCE), was identified in glomerular mesangial cells, tubular epithelium, and renovascular smooth muscle cells. The physiological and pathological relevance and the characterization of SOCC complexes in those cells are still unclear. In this review, we summarize the current knowledge of SOCC and their roles in renal glomerular, tubular and vascular cells, including studies from our laboratory, emphasizing SOCE regulation of fibrotic protein deposition. Understanding the diverse roles of SOCE in different renal cell types is essential, as SOCC and its signaling pathways are emerging targets for treatment of SOCE-related diseases.

Keywords: Orai1; STIM1; Store-operated Ca2+ channels; TRPC; extracellular matrix; kidney disease; mesangial cells.

Figure 1.

Mediators and modulators of store-operated Ca²⁺ entry in glomerular mesangial cells. Panel (a): Endoplasmic reticular (ER) Ca²⁺ depletion activates store-operated Ca²⁺ entry (SOCE) via STIM1. Activation of G-protein coupled receptors (GPCR) or receptor tyrosine kinases activates phospholipase C (PLC), which hydrolyzes phosphatidylinositol bisphosphate (PIP₂), generating inositol trisphosphate (IP₃). Interaction of IP₃ with its ER receptor provokes Ca²⁺ release, depleting the ER Ca²⁺ store. ER Ca²⁺ depletion causes conformational changes in STIM1 that activate Orai1:Orai1 homodimeric and/or Orai1: transient receptor potential canonical (TRPC) heterodimeric store-operated Ca²⁺ channels in the plasma membrane and, thus, SOCE. Panel (b): Factors modulating SOCE via TRPC channels. STIM1-activated TRPC1- and TRPC4-mediated Ca²⁺ entry are suppressed, respectively, by micro RNA 135a (miR135a) and the nitric oxide (NO)—cyclic GMP (cGMP)—protein kinase G (PKG)—vasodilator-stimulated phosphoprotein (VASP) cascade. TRPC1-mediated SOCE inhibits extracellular matrix (ECM) synthesis, while available evidence suggests urotensin II-induced TRPC4-mediated SOCE activates ECM synthesis. TRPC:Orai1 heterodimers are shown, but the association of TRPC and Orai1 has not been established unequivocally; thus, SOCE may proceed via TRPC1 or TRPC4 alone. Transforming growth factor β1 (TGFβ1) and high extracellular glucose concentrations suppress TRPC1-mediated SOCE by activating miR135a expression, while urotensin II and high glucose activate TRPC4-mediated SOCE. Panel (c): Factors modulating SOCE via Orai1 homodimers, and SOCE-inhibited ECM synthesis. Orai1-mediated SOCE is activated by STIM1, protein kinase C (PKC) α, and glucagon-like peptide-1 receptor (GLP-1R), and inhibited by PKC β₁. SOCE suppresses ECM synthesis directly, and indirectly by (1) activating release of interleukin-6 (IL6) which, upon binding its receptor (IL6-R), activates GLP-1R, and (2) inhibiting TGFβ1-receptor (TGFβ1R) activation of smad 1 and 3 phosphorylation.

Figure 2.

Increased glomerular ECM protein content in mice after in vivo knockdown of Orai1 in MCs using targeted nanoparticle (NP) delivery system with Cy3 tagged siOrai1. Panels (a), (b): Immunoblot analysis of renal cortex extracts showing fibronectin (FN) content in the cortex of kidney from the mice treated with control NP (NP-Con) and NP-Cy3-siOrai1 (knockdown of Orai1). Tubulin-α (TB) is a loading control. Panel (a): representative immunoblot; panel (b): summary data. *P < 0.05 vs. NP-Con. Panels (c) and (d): immunohistochemistry showing abundance of (c) FN and (d) collagen IV (Col IV) in glomeruli of the mice treated with NP-Con and NP-Cys-siOrai1. Both FN and Col IV are stained green. In NP-Con, a bright-field image was captured to show the glomerulus. In NP-Cy3-siOrai1, the distribution of NP-Cy3-siOrai1 is indicated by Cy3 signals (red). Arrows indicate glomeruli. Original magnification ×200. (Adapted from Wu et al.).

Figure 3.

Tubular and microvascular locations of dysfunctional SOCE in renal diseases. The boxes represent different locations within the nephron and renal microvasculature. Blue text identifies the clinical pathologies related to SOCE in each location, and black text lists possible effects of SOCE in the different renal cell types. TRPC: transient receptor potential canonical; ECM: extracellular matrix; SOCE: store-operated Ca²⁺ entry; STIM: stromal interaction molecule; EMT: epithelial-mesenchymal transition; cAMP: cyclic AMP; ER: endoplasmic reticulum; AQP: aquaporin.