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JGA‐Derived CCN1 is a Systemically Acting Angiogenic Hormone

The kidneys are major regulatory organs of whole body homeostasis including body fluid and electrolyte balance, blood pressure maintenance, and blood cell production. Renal control mechanisms of these key systemic physiological functions include the local production and secretion of peptide hormones, and their actions at distant organ sites. Classic examples are erythropoietin, and renin, which is released from the highly perfused juxtaglomerular apparatus (JGA). The present studies aimed to test the hypothesis that the newly identified JGA‐derived cysteine‐rich protein CCN1 is released into the blood and serves as a novel systemic angiogenic hormone promoting general cardiovascular health. Blood was collected before and at different times after bilateral nephrectomy in both mice and rats. Plasma CCN1 levels measured by CCN1 ELISA and immunoblotting continuously decayed after nephrectomy, suggesting that the kidney/JGA is a significant source of systemic CCN1. Immunostaining of mouse and human kidneys showed a robust and constitutive expression of CCN1 in the JGA. The tube formation assay of glomerular endothelial cells (GEnCs) was performed to test the effect of exogenous CCN1 on in vitro angiogenesis. CCN1 appeared to be more effective on in vitro angiogenesis than the gold‐standard angiogenic factor VEGF. Other classic in vitro assays of GEnC cell proliferation and cell migration (scratch opening assay) showed similar robust effects of CCN1. In vivo, CD34 immunostaining of kidney tissues collected from C57BL/6 mice treated with subcapsular injection of CCN1 peptide showed a significant increase of angiogenesis compared to untreated mice. Kidney, aorta, heart, and brain tissues were collected from mice with JGA‐specific CCN1 KO before and three weeks after tamoxifen induction, and sections stained for TUNEL assay of apoptosis. Compared to nearly undetectable levels in normal tissues before, a high number of vascular endothelial cells in all tissues stained TUNEL+ after JGA CCN1 deletion, indicating the presence of widespread systemic endothelial injury when renal CCN1 synthesis is compromised. These findings provide strong support for our new concept that JGA‐derived CCN1 is released into the blood, acts as a new systemic angiogenic hormone, and is essential for maintaining vascular integrity throughout the body.