for the therapeutic potential of PGRN in hHcys-induced cardiorenal dysfunction, which was associated with the negative regulation of Wnt/β-catenin signaling. Materials and MethodsAn extended Materials and Methods section can be found in the online-only Data Supplement. AnimalsTwelve-week-old male PGRN-deficient (Grn −/− ) mice and wild-type C57BL/6 mice were purchased from the Jackson laboratory (Bar Harbor, ME).Abstract-Hyperhomocysteinemia (hHcys) is an important independent risk factor for the development of cardiovascular disease and end-stage renal disease. Although multiple approaches lowering the levels of homocysteine have been used in experimental studies and clinical trials, there is no effective therapy available to fully prevent homocysteineinduced injury. Therefore, identifying key molecules in the pathogenic pathways may provide clues to develop new therapeutic strategies for the treatment of hHcys-associated injury beyond lowering the plasma homocysteine levels. In this study, we found that the levels of progranulin (PGRN), an autocrine growth factor, were significantly reduced in the kidney and heart from a mouse model of hHcys. We further observed that in hHcys, PGRN-deficient mice significantly exacerbated cardiorenal injury as evidenced by higher levels of urinary albumin excretion, more severe renal morphological injuries, including pronounced glomerular basement membrane thickening and podocyte foot process effacement, and adverse myocardial remodeling versus wild-type mice. Mechanistically, we found that PGRNmedicated Wnt/β-catenin signaling was one of the critical signal transduction pathways that links homocysteine to cardiorenal injury. Importantly, we finally provided direct evidence for the therapeutic potential of PGRN in mice with hHcys by pretreatment with recombinant human PGRN. Collectively, our results suggest that PGRN may be an innovative therapeutic strategy for treating patients with hHcys. (Hypertension. 2017;69:259-266.

Podocyte injury is a major determinant of focal segmental glomerular sclerosis (FSGS) and the identification of potential therapeutic targets for preventing podocyte injury has clinical importance for the treatment of FSGS. CLEC14A is a single‐pass transmembrane glycoprotein belonging to the vascular expressed C‐type lectin family. CLEC14A is found to be expressed in vascular endothelial cells during embryogenesis and is also implicated in tumor angiogenesis. However, the current understanding of the biological functions of CLEC14A in podocyte is very limited. In this study, we found that CLEC14A was expressed in podocyte and protected against podocyte injury in mice with Adriamycin (ADR)‐induced FSGS. First, we observed that CLEC14A was downregulated in mice with ADR nephropathy and renal biopsies from individuals with FSGS and other forms of podocytopathies. Moreover, CLEC14A deficiency exacerbated podocyte injury and proteinuria in mice with ADR nephropathy accompanied by enhanced inflammatory cell infiltration and inflammatory responses. In vitro, overexpression of CLEC14A in podocyte had pleiotropic protective actions, including anti‐inflammatory and anti‐apoptosis effects. Mechanistically, CLEC14A inhibited high‐mobility group box 1 protein (HMGB1) release, at least in part by directly binding HMGB1, and suppressed HMGB1‐mediated signaling, including NF‐κB signaling and early growth response protein 1 (EGR1) signaling. Taken together, our findings provide new insights into the pivotal role of CLEC14A in maintaining podocyte function, indicating that CLEC14A may be an innovative therapeutic target in FSGS.