Abstract: TH-PO253
Blockade of Sonic Hedgehog Signaling in Fibroblasts Protects against AKI
Session Information
- AKI Basic: Cell Death and Biomarkers
November 02, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Acute Kidney Injury
- 001 AKI: Basic
Authors
- Zhou, Dong, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Fu, Haiyan, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Tian, Yuan, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Mo, Hongyan, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Liu, Youhua, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Background
Sonic Hedgehog (Shh), an evolutionarily conserved, secreted and extracellular signal protein, is an inducible, tubule-derived growth factor specifically promoting fibroblast proliferation and expansion through its receptor by the so-called canonical pathway in chronic kidney disease. However, whether activation of Shh signaling in fibroblast plays any role in acute kidney injury (AKI) remains to be defined.
Results
Here we show that Shh, Smoothened (Smo) and fibroblasts were concomitantly activated after ischemic AKI. To investigate the potential role of activation of fibroblast-specific Shh signaling in AKI, we generated conditional knockout mice, designated as FC-Smo-/-, in which the Smo gene was specifically disrupted in renal fibroblasts by using the inducible Cre-LoxP system. The FC-Smo-/- mice are phenotypically normal and displayed no appreciable defects in kidney morphology and function. However, in AKI induced by ischemia reperfusion injury (IRI), loss of fibroblasts Smo substantially ameliorated renal dysfunction and lesions. Compared with controls, FC-Smo-/- mice displayed lower serum creatinine and reduced morphologic injury. Fibroblast-specific ablation of Smo significantly blocked the expression of pro-inflammatory cytokines including TNF-α and MCP-1, and retarded renal infiltration of inflammatory cells such as CD3+ T cells and F4/80+ macrophages after AKI. Less apoptosis was detected in FC-Smo-/- kidneys, accompanied by a decreased expression of Bax and Fas-associated protein with death domain (FADD). Interestingly, loss of Smo in fibroblast in turn caused an increased expression of Shh in tubules by feedback control, Shh then promoted activation of canonical Wnt signaling pathway including upregulation of the majority of 19 Wnt family members after AKI which is strongly associated with AKI recovery.
Conclusion
Collectively, these results suggest that loss of fibroblast-specific Shh receptor, Smo, is crucial in conferring renal protection after AKI, primarily via a reduced renal inflammation, as well as activation of Wnt signaling through cell-cell communication.
Funding
- NIDDK Support