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Store-operated Ca2+ signaling in kidney glomerular mesangial cells

肾小球系膜细胞中钙池操纵的 Ca2 信号传导

基本信息

批准号：
10066344
负责人：
RONG MA
金额：
$ 32.85万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10066344
关键词：
Address Affect C57BLKS/J Mouse Cell physiology Cells Development Diabetes Mellitus Diabetic Nephropathy Diabetic mouse Down-Regulation Employment End stage renal failure Extracellular Matrix Proteins Family Functional disorder Genetic Glomerular Mesangial Cell Glucose Goals Histology Homer 1 Human Impairment In Vitro Injury Injury to Kidney Kidney Kidney Diseases Kidney Failure Lesion Light Mediating Modeling Molecular Mus Pathogenesis Pathologic Pathway interactions Patients Pilot Projects Play Production Protein Isoforms Proteins Renal function Role Signal Transduction Source Structure Structure of glomerular mesangium System Testing Therapeutic Intervention Time Up-Regulation clinically significant db/db mouse diabetes management diabetic gene delivery system glomerulosclerosis in vivo inhibitor/antagonist knock-down mesangial cell nanoparticle new therapeutic target non-diabetic novel protein expression therapeutic target

项目摘要

Diabetic nephropathy (DN) is the most common cause of end stage renal disease. The early features of DN include accumulation of extracellular matrix (ECM) proteins in glomerulus, which if not treated, will develop to glomerulosclerosis and renal insufficiency. Therefore, a therapeutic intervention on the pathological changes can slow the progression of DN. However, there are no known therapies currently available that can treat the progressive lesion of glomerular histology and loss of renal function in DN. Glomerular mesangial cell (MC) is the major source of mesangial matrix. Overproduction of ECM proteins by MCs contributes to glomerular damage in early DN. We have previously shown that MC function is regulated by store-operated Ca2+ channel (SOC). The Ca2+ signaling mediated by this channel is multi-functional and the function of SOC is cell context dependent. In glomerular MCs, we recently found that SOC suppressed ECM protein expression. Our findings, for the first time, demonstrate that SOC-mediated Ca2+ signaling in MCs is an anti-fibrotic mechanism and thus, upregulating SOC function in MCs could be beneficial for kidney affected by diabetes. Recently, several small cytosolic proteins have been found to function as endogenous suppressors of SOC. Our pilot studies showed that high glucose treatment and/or diabetes increased protein abundance of at least one of the SOC inhibitory molecules in MCs and/or glomerulus. Furthermore, over expression of I-mfa significantly inhibited SOC- mediated Ca2+ signaling and increased abundance of ECM proteins in cultured human MCs. Moreover, in vitro and in vivo downregulation of SOC function significantly increased ECM proteins. We also found that activation of SOC in cultured MCs markedly inhibited Smad3 signaling, a pathway that plays a crucial role in renal injury by diabetes. Consistently, in vivo inhibition of SOC function activated Smad3 in mouse glomerulus. These findings raise a possibility that dysfunction of SOC in MCs contributes to renal injury in diabetes and thus, this Ca2+ signaling could be a therapeutic target for DN. We thereby, hypothesize that upregulating SOC function in MCs protects kidney from diabetes-induced renal injury by inhibiting the TGF-β1/Smad3 pathway. Three specific Aims will be addressed using both in vitro and in vivo systems. Aim I will determine that in vivo inhibition of SOC function in MCs impairs glomerular structure and function in non diabetic mice, and aggravates renal injury in mice with DN. Aim II will investigate that in vivo upregulation of SOC function in MCs by knocking down endogenous suppressors of SOC ameliorates renal injury in mice with DN. Aim III will delineate mechanistic pathways by which SOC inhibits ECM protein expression in MCs using both in vitro and in vivo systems, focusing on TGF-β1/Smad3 signaling. This novel study will identify a new therapeutic target for DN. In addition, we will establish a novel in vivo nanoparticle gene delivery system which specifically target on glomerular MCs. Successful employment of the MC specific in vivo delivery approach has clinical significance in treating MC-associated kidney diseases.