Therapeutic Potential of Progranulin in Hyperhomocysteinemia-Induced Cardiorenal Dysfunction

Abstract

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.

Temporal patterns of macrophage‐ and neutrophil‐related markers are associated with clinical outcome in heart failure patients

“…Our results may be therefore viewed as hypothesis generating and indicate a need for further studies. The equivocal role of progranulin is further illustrated by the fact that it exerted a stimulatory effect on insulin resistance, which goes in line with our observation on higher GRN levels in diabetic patients, but there is also evidence of its beneficial role in reducing renal and cardiac damage in animal models …”

Progranulin serum levels in human kidney transplant recipients: A longitudinal study

“…Moreover, administration of recombinant PGRN before LPS treatment in wild-type mice was associated with reduced renal injury [ 37 ]. Finally, in a mice model of hyperhomocysteinemia (a risk factor for kidney disease), PGRN-deficient mice also presented exacerbated renal injury, that could be ameliorated by pretreatment with recombinant human PGRN [ 38 ]. In this context, PGRN could be a renal protective molecule in an inflammatory environment.…”

TIPE1 suppresses invasion and migration through down‐regulating Wnt/β‐catenin pathway in gastric cancer

“…Mechanistically, we found that TIPE1 negatively regulated Wnt signalling which is an evolutionarily conserved developmental signalling cascade that exhibits a pivotal function in regulating a variety of biologic processes . The canonical Wnt pathway is also known as the Wnt/β‐catenin pathway as β‐catenin is a key transducer of the Wnt signal from the cytoplasm to the nucleus.…”