Coronary heart disease (CHD) is the leading cause of death in the Unites States and globally. The administration of growth factors to preserve cardiac function after myocardial infarction (MI) is currently being explored. Basic fibroblast growth factor (bFGF), a potent angiogenic factor has poor clinical efficacy due to its short biological half-life and low plasma stability. The goal of this study was to develop bFGF-loaded polycaprolactone (PCL) microspheres for sustained release of bFGF and to evaluate its angiogenic potential. The bFGF-PCL microspheres (bFGF-PCL-MS) were fabricated using the emulsion solvent-evaporation method and found to have spherical morphology with a mean size of 4.21 ± 1.28 µm. In vitro bFGF release studies showed a controlled release for up to 30 days. Treatment of HUVECs with bFGF-PCL-MS in vitro enhanced their cell proliferation and migration properties when compared to the untreated control group. Treatment of HUVECs with release media from bFGF-PCL-MS also significantly increased expression of angiogenic genes (bFGF and VEGFA) as compared to untreated cells. The in vivo angiogenic potential of these bFGF-PCL-MS was further confirmed in rats using a Matrigel plug assay with subsequent immunohistochemical staining showing increased expression of angiogenic markers. Overall, bFGF-PCL-MS could serve as a potential angiogenic agent to promote cell survival and angiogenesis following an acute myocardial infarction.

Idiopathic nephrotic syndrome (INS) is a podocyte disease triggered by immune-derived factors. Endothelial activation occurs in this context, but whether the activated endothelium contributes to podocyte injury is unknown. We tested the hypothesis that CD93, a protein primarily expressed in the endothelium, is a contributory factor of podocyte injury. We studied 460 patients with INS and 150 with other podocytopathies. CD93 was analyzed in kidney tissue, urine, and serum samples. We tested the efficacy of CD93 blockade in vitro and in vivo and investigated the relationship between soluble CD93 and clinical outcomes in human INS. CD93 was highly expressed by glomerular endothelial cells (GEnCs) in human INS, and INS sera stimulated cultured human GEnCs to release CD93. Mechanistically, soluble CD93 mediated podocyte activation via β1 integrin/FAK signaling in cultured human podocytes. CD93 blockade mitigated the activation of cultured human podocytes and albumin permeability in human GEnC-podocyte cocultures as well as albuminuria, glomerulosclerosis, and podocyte loss in two models of nephrotic syndrome: podocyte-specific transforming growth factor–β1 signaling ( PodTgfbr1 ) mice and adriamycin-treated mice. Cd93 knockout mice showed less proteinuria and glomerulosclerosis, compared with controls, after adriamycin injection. In patients with INS, soluble CD93 was high in urine in ~90% and 50% of patients in relapse and remission, respectively. High urinary CD93 was associated with faster decline in kidney function and slower response to immunosuppression. Soluble and glomerular CD93 was also elevated in other podocytopathies. We conclude that soluble CD93 contributes to podocyte injury.

Idiopathic nephrotic syndrome (NS) is a common glomerular disease. Although glucocorticoids (GC) are the primary treatment, the PPARγ agonist pioglitazone (Pio) also reduces proteinuria in patients with NS and directly protects podocytes from injury. Because both drugs reduce proteinuria, we hypothesized these effects result from overlapping transcriptional patterns. Systems biology approaches compared glomerular transcriptomes from rats with PAN-induced NS treated with GC vs. Pio and identified 29 commonly regulated genes-of-interest, primarily involved in extracellular matrix (ECM) remodeling. Correlation with clinical idiopathic NS patient datasets confirmed glomerular ECM dysregulation as a potential mechanism of injury. Cellular deconvolution in silico revealed GC- and Pio-induced amelioration of altered genes primarily within podocytes and mesangial cells. While validation studies are indicated, these analyses identified molecular pathways involved in the early stages of NS (prior to scarring), suggesting that targeting glomerular ECM dysregulation may enable a future non-immunosuppressive approach for proteinuria reduction in idiopathic NS.