Adiponectin promotes monocyte-to-fibroblast transition in renal fibrosis

Jun Yang, Song Chang Lin, Gang Chen, Liqun He, Zhaoyong Hu, Lawrence Chan, Jo Ann Trial, Mark L. Entman, Yanlin Wang

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

Abstract

Bone marrow-derived fibroblasts may contribute substantially to the pathogenesis of renal fibrosis through the excessive production and deposition of extracellular matrix. However, the mechanisms underlying the accumulation and activation of these fibroblasts are not understood. Here, we used a mouse model of tubulointerstitial fibrosis to determine whether adiponectin, which is elevated in CKD and is associated with disease progression, regulates monocyte-to-fibroblast transition and fibroblast activation in injured kidneys. In wild-type mice, the expression of adiponectin and the number of bone marrow-derived fibroblasts in the kidney increased after renal obstruction. In contrast, the obstructed kidneys of adiponectin-knockout mice had fewer bone marrow-derived fibroblasts. Adiponectin deficiency also led to a reduction in the number ofmyofibroblasts, the expression of profibrotic chemokines and cytokines, and the number of procollagen-expressing M2 macrophages in injured kidneys. Consistent with these findings, adiponectin-deficiency reduced the expression of collagen I and fibronectin. Similar results were observed in wild-type and adiponectin-knockout mice after ischemia-reperfusion injury. In cultured bone marrow-derived monocytes, adiponectin stimulated the expression of a-smooth muscle actin (SMA) and extracellular matrix proteins and activated AMP-activated protein kinase (AMPK) in a time- and dose-dependent manner. Furthermore, specific activation of AMPK increased the expression of α-SMA and extracellular matrix proteins, while inhibition of AMPK attenuated these responses. Taken together, these findings identify adiponectin as a critical regulator of monocyte-to-fibroblast transition and renal fibrosis, suggesting that inhibition of adiponectin/AMPK signaling may represent a novel therapeutic target for fibrotic kidney disease.

Original languageEnglish (US)
Pages (from-to)1644-1659
Number of pages16
JournalJournal of the American Society of Nephrology
Volume24
Issue number10
DOIs
StatePublished - Oct 2013

ASJC Scopus subject areas

  • Medicine(all)

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