Store-operated Ca2+ channel signaling: Novel mechanism for podocyte injury in kidney disease

Abstract

Studies over the last decade have markedly broadened our understanding of store-operated Ca²⁺ channels (SOCs) and their roles in kidney diseases and podocyte dysfunction. Podocytes are terminally differentiated glomerular visceral epithelial cells which are tightly attached to the glomerular capillary basement membrane. Podocytes and their unique foot processes (pedicels) constitute the outer layer of the glomerular filtration membrane and the final barrier preventing filtration of albumin and other plasma proteins. Diabetic nephropathy and other renal diseases are associated with podocyte injury and proteinuria. Recent evidence demonstrates a pivotal role of store-operated Ca²⁺ entry (SOCE) in maintaining structural and functional integrity of podocytes. This article reviews the current knowledge of SOCE and its contributions to podocyte physiology. Recent studies of the contributions of SOC dysfunction to podocyte injury in both cell culture and animal models are discussed, including work in our laboratory. Several downstream signaling pathways mediating SOC function in podocytes also are examined. Understanding the pivotal roles of SOC in podocyte health and disease is essential, as SOCE-activated signaling pathways are potential treatment targets for podocyte injury-related kidney diseases.

Keywords: Ca2+ signaling; Orai1; STIM1; kidney disease; podocyte; proteinuria; store-operated Ca2+ channel.

Figure 1.

Podocyte structure and connections with glomerular basement membrane. CD2AP: CD2-associated protein; ER: endoplasmic reticulum; GBM: glomerular basement membrane; Neph1: nephrin 1; SD: slit diaphragm; STIM1: stromal interaction molecule 1; TRPC6: transient receptor potential.

Figure 2.

Confocal microscopic images, showing contribution of SOCE to podocyte cytoskeleton organization. (A & B): Representative immunofluorescence staining of F-actin of podocytes with different treatments. (C & D): Statistical analysis of data from experiments presented in A and B, respectively (Adapted from Tao et al. with permission of the American Society for Biochemistry and Molecular Biology).

Figure 3.

SOCE-initiated signaling pathways in podocytes. In diabetic nephropathy and many other kidney diseases, the activities of one or more of these pathways are upregulated and the increased signaling results in podocyte injury. Broken arrows: putative triggers of the signaling pathways. EMT: epithelial–mesenchymal transition; ER: endoplasmic reticulum; SOCE: store-operated Ca²⁺ entry; STIM1: stromal interaction molecule 1.