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Abstract: TH-PO920

SMOC2 Mediates Renal Fibrosis by Activation of Inflammation and Fibroblast to Myofibroblast Differentiation

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Author

  • Xin, Cuiyan, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States

Group or Team Name

  • Vaidya Lab
Background

Fibrosis is a common end stage of nearly all chronic inflammatory organ diseases including chronic kidney diseases (CKD). Secreted modular calcium-binding protein 2 (SMOC2) belongs to the secreted protein acidic and rich in cysteine (SPARC) family of matricellular proteins whose members are known to modulate cell-matrix interactions. SMOC2 has been shown to contribute to CKD by regulating initiation and progression of kidney fibrosis. We therefore investigated the mechanisms responsible for signaling activation pathways by SMOC2 resulting in its fibrogenic effect.

Methods

To determine SMOC2 expression in CKD, three mice CKD models were employed: Alport nephropathy mice model (caused by a null mutation of the a3 chain of collagen type IV), RNA-Seq was performed to determine extracellular matrix genes in this model; Parabiotic aging model generated by parabiosis sugery for 4 weeks and unilateral ureter obstruction (UUO) surgery in 5 and 10 days, separately; Sequential ischemia-nephrectomy CKD model was generated by bilateral ischemia reperfusion (Bi-IRI) and unilateral nephrectomy surgeries time-dependently. RT-PCR and western-blot were employed to determine fibrotic gene mRNA and protein expression in these three models. To investigate the mechanism of SMOC2 triggered fibrogenesis and activation of fibrogenic signaling pathways, SMOC2 protein was used to stimulate interstitial fibroblasts and human primary proximal tubular epithelial cells.

Results

We found that SMOC2 is in the top 10 DEGs of extracellular matrix genes in Alport mice. SMOC2 gene and protein were highly expressed in Col4a3 knockout (KO) mice tissue compared to wildtype (WT) mice. Furthermore, SMOC2 over expression in fibrosis was also confirmed in parabiotic-UUO kidney disease model and in-house developed CKD model. Mechanistically, SMOC2 activates Smad and MAPK signaling in fibroblast and proximal tubular epithelial cells, which are both inhibited by TGFbRI inhibitor (SB431542) and MAPK p42/44 inhibitor (U0126). SMOC2 also promotes inflammatory gene expression such as IL-6 and TNFa.

Conclusion

SMOC2 is a key signaling molecule mediating fibrogenesis, and modulating of SMOC2 may provide a new potential therapeutic target for chronic kidney diseases.

Funding

  • NIDDK Support