Therapeutic potential of PGRN
in hyperhomocysteinemia-induced cardiorenal dysfunction
Yi Fu1#, Yu Sun1#, Meng
Zhou1, Xiaojie Wang1, Ziying Wang1, Xinbing
Wei1, Yan Zhang1, Zeyu Su1, Kaili
Liang1, Wei
Tang2, and Fan Yi1*
1Department of
Pharmacology, Shandong University School
of Medicine, Jinan, China, 250012
2 Department of Biochemistry and Molecular Biology, Shandong
University School
of Medicine, Jinan, China, 250012
#Co-first authors,
equally contributed to this work
Running title: Progranulin
and homocysteine
*Send Correspondence and Reprint Requests to:
Fan Yi, Ph.D
Department of
Pharmacology
Shandong University School of Medicine
44#, Wenhua Xi Road,
Jinan, Shandong,
250012, P.R. China
Phone : 86-0531-88382616
Fax : 86-0531-88382616
E-mail: fanyi@sdu.edu.cn
Abstract
Hyperhomocysteinemia (hHcys) is an important independent
risk factor for the development of cardiovascular disease (CVD) and end stage
renal disease (ESRD). Although multiple
approaches lowering the levels of homocysteine
(Hcys) have been used in experimental studies and clinical trials, there is no
effective therapy available to fully prevent Hcys-induced 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 Hcys 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 (GBM) thickening and podocyte foot process effacement, and adverse myocardial remodeling versus wild
type mice. Mechanistically, we found that PGRN-medicated Wnt/β-catenin
signaling was one of the critical signal transduction pathways that links Hcys
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 (rPGRN). Collectively, our results suggest that PGRN may be an innovative therapeutic strategy for
treating patients with hHcys.
