title: Therapeutic Potential of Progranulin in Hyperhomocysteinemia-Induced Cardiorenal Dysfunction.
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 homocysteine-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 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 PGRN-medicated 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.
authors.affiliation: From the Departments of Pharmacology (Y.F., Y.S., M.Z., X. Wang, Z.W., X. Wei, Y.Z., Z.S., K.L., F.Y.) and Pathogenic Biology (W.T.), Shandong University School of Medicine, Jinan, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Fu
authors.affiliation: From the Departments of Pharmacology (Y.F., Y.S., M.Z., X. Wang, Z.W., X. Wei, Y.Z., Z.S., K.L., F.Y.) and Pathogenic Biology (W.T.), Shandong University School of Medicine, Jinan, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: From the Departments of Pharmacology (Y.F., Y.S., M.Z., X. Wang, Z.W., X. Wei, Y.Z., Z.S., K.L., F.Y.) and Pathogenic Biology (W.T.), Shandong University School of Medicine, Jinan, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhou
authors.affiliation: From the Departments of Pharmacology (Y.F., Y.S., M.Z., X. Wang, Z.W., X. Wei, Y.Z., Z.S., K.L., F.Y.) and Pathogenic Biology (W.T.), Shandong University School of Medicine, Jinan, China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Wang
authors.affiliation: From the Departments of Pharmacology (Y.F., Y.S., M.Z., X. Wang, Z.W., X. Wei, Y.Z., Z.S., K.L., F.Y.) and Pathogenic Biology (W.T.), Shandong University School of Medicine, Jinan, China.
authors.forename: Ziying
authors.initials: Z
authors.lastname: Wang
authors.affiliation: From the Departments of Pharmacology (Y.F., Y.S., M.Z., X. Wang, Z.W., X. Wei, Y.Z., Z.S., K.L., F.Y.) and Pathogenic Biology (W.T.), Shandong University School of Medicine, Jinan, China.
authors.forename: Xinbing
authors.initials: X
authors.lastname: Wei
authors.affiliation: From the Departments of Pharmacology (Y.F., Y.S., M.Z., X. Wang, Z.W., X. Wei, Y.Z., Z.S., K.L., F.Y.) and Pathogenic Biology (W.T.), Shandong University School of Medicine, Jinan, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Departments of Pharmacology (Y.F., Y.S., M.Z., X. Wang, Z.W., X. Wei, Y.Z., Z.S., K.L., F.Y.) and Pathogenic Biology (W.T.), Shandong University School of Medicine, Jinan, China.
authors.forename: Zeyu
authors.initials: Z
authors.lastname: Su
authors.affiliation: From the Departments of Pharmacology (Y.F., Y.S., M.Z., X. Wang, Z.W., X. Wei, Y.Z., Z.S., K.L., F.Y.) and Pathogenic Biology (W.T.), Shandong University School of Medicine, Jinan, China.
authors.forename: Kaili
authors.initials: K
authors.lastname: Liang
authors.affiliation: From the Departments of Pharmacology (Y.F., Y.S., M.Z., X. Wang, Z.W., X. Wei, Y.Z., Z.S., K.L., F.Y.) and Pathogenic Biology (W.T.), Shandong University School of Medicine, Jinan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.affiliation: From the Departments of Pharmacology (Y.F., Y.S., M.Z., X. Wang, Z.W., X. Wei, Y.Z., Z.S., K.L., F.Y.) and Pathogenic Biology (W.T.), Shandong University School of Medicine, Jinan, China. fanyi@sdu.edu.cn.
authors.forename: Fan
authors.initials: F
authors.lastname: Yi
mesh_terms: D000818:Animals; D059347:Cardio-Renal Syndrome / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004452:Echocardiography; D000077155:Granulins; D006710:Homocysteine / Q000097:blood; D020138:Hyperhomocysteinemia / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D036341:Intercellular Signaling Peptides and Proteins / Q000627:therapeutic use*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D000077153:Progranulins; D011994:Recombinant Proteins / Q000627:therapeutic use
chemical_list: D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D011994:Recombinant Proteins; D006710:Homocysteine
keywords: PGRN; Wnt pathway; cardiac hypertrophy; glomerular filtration barrier; homocysteine