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J Am Soc Nephrol. 2015 Mar;26(3):636-46. doi: 10.1681/ASN.2014020210. Epub 2014 Jul 28.

Cardiac myocyte-derived follistatin-like 1 prevents renal injury in a subtotal nephrectomy model.

Author information

1
Departments of *Cardiology and.
2
Molecular Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan; nouchi@med.nagoya-u.ac.jp ohashik@med.nagoya-u.ac.jp.
3
Department of Anatomy, Embryology & Physiology, Heart Failure Research Center, Academic Medical Center, Amsterdam, The Netherlands; and.
4
Molecular Cardiology, Boston University School of Medicine, Boston, Massachusetts.

Abstract

Heart disease contributes to the progression of CKD. Heart tissue produces a number of secreted proteins, also known as cardiokines, which participate in intercellular and intertissue communication. We recently reported that follistatin-like 1 (Fstl1) functions as a cardiokine with cardioprotective properties. Here, we investigated the role of cardiac Fstl1 in renal injury after subtotal nephrectomy. Cardiac-specific Fstl1-deficient (cFstl1-KO) mice and wild-type mice were subjected to subtotal (5/6) nephrectomy. cFstl1-KO mice showed exacerbation of urinary albumin excretion, glomerular hypertrophy, and tubulointerstitial fibrosis after subtotal renal ablation compared with wild-type mice. cFstl1-KO mice also exhibited increased mRNA levels of proinflammatory cytokines, including TNF-α and IL-6, NADPH oxidase components, and fibrotic mediators, in the remnant kidney. Conversely, systemic administration of adenoviral vectors expressing Fstl1 (Ad-Fstl1) to wild-type mice with subtotal nephrectomy led to amelioration of albuminuria, glomerular hypertrophy, and tubulointerstitial fibrosis, accompanied by reduced expression of proinflammatory mediators, NADPH oxidase components, and fibrotic markers in the remnant kidney. In cultured human mesangial cells, treatment with recombinant FSTL1 attenuated TNF-α-stimulated expression of proinflammatory cytokines. Treatment of mesangial cells with FSTL1 augmented the phosphorylation of AMP-activated protein kinase (AMPK), and inhibition of AMPK activation abrogated the anti-inflammatory effects of FSTL1. These data suggest that Fstl1 functions in cardiorenal communication and that the lack of Fstl1 production by myocytes promotes glomerular and tubulointerstitial damage in the kidney.

KEYWORDS:

albuminuria; cardiovascular; cell signaling; chronic inflammation; mesangial cells; renal injury

PMID:
25071081
PMCID:
PMC4341480
DOI:
10.1681/ASN.2014020210
[Indexed for MEDLINE]
Free PMC Article

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