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Review
. 2016 Sep;59(9):920-9.
doi: 10.1007/s11427-016-0020-y. Epub 2016 Jun 22.

Sonic hedgehog signaling in kidney fibrosis: a master communicator

Dong Zhou  1 , Roderick J Tan  2 , Youhua Liu  3   4
Affiliations
Review

Sonic hedgehog signaling in kidney fibrosis: a master communicator

Dong Zhou et al. Sci China Life Sci. 2016 Sep.

Abstract

The hedgehog signaling cascade is an evolutionarily conserved pathway that regulates multiple aspects of embryonic development and plays a decisive role in tissue homeostasis. As the best studied member of three hedgehog ligands, sonic hedgehog (Shh) is known to be associated with kidney development and tissue repair after various insults. Recent studies uncover an intrinsic link between dysregulated Shh signaling and renal fibrogenesis. In various types of chronic kidney disease (CKD), Shh is upregulated specifically in renal tubular epithelium but targets interstitial fibroblasts, thereby mediating a dynamic epithelial- mesenchymal communication (EMC). Tubule-derived Shh acts as a growth factor for interstitial fibroblasts and controls a hierarchy of fibrosis-related genes, which lead to the excessive deposition of extracellular matrix in renal interstitium. In this review, we recapitulate the principle of Shh signaling, its activation and regulation in a variety of kidney diseases. We also discuss the potential mechanisms by which Shh promotes renal fibrosis and assess the efficacy of blocking this signaling in preclinical settings. Continuing these lines of investigations will provide novel opportunities for designing effective therapies to improve CKD prognosis in patients.

Keywords: Gli; Sonic hedgehog; fibroblast; renal fibrosis; tubular cells.

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Conflict of interest statement

Compliance and ethics The author(s) declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Schematic illustration of the Shh signaling pathway. A, In Shh-producing cells, the Shh precursor is proteolytically cleaved to generate the N-Shh in the endoplasmic reticulum (ER). Secreted Shh contains two covalent cholesterol modifications: a C-terminal cholesterol moiety and a palmitoyl group is added at the N-terminus. Skn and Dispatched, mediate the release of Shh ligand. B, The canonical Shh signaling. In the inactive state, the transmembrane protein receptor Ptch1 interacts with and inhibits the activity of a seven transmembrane protein, Smo. Interactions with cytoplasmic proteins, including Fused and Sufu, the transcription factors Gli are prevented from entering the nucleus and downstream target genes expression are repressed. In the active state, Shh binding to Ptch1, which allows Smo activation, thereby activating the cascade that leads to the Gli transcription factors to exert their effects in the nucleus. C, The non-canonical Shh signaling. There are two types of non-canonical Shh signaling pathways, one is Ptch1-dependent which regulates cell apoptosis and proliferation, the second is Smo-dependent which associate with modulation of actin cytoskeleton-dependent processes. Shh, Sonic hedgehog. N-Shh, N-terminal Sonic hedgehog. Skn, Skinny hedgehog. Ptch1, Patched-1. Smo, Smoothened. Hhip1, Hedgehog-interacting protein 1. Fu, Fused. Sufu, Suppressor of fused. Gli, Glioma-associated oncogenes.
Figure 2
Figure 2
Tubule-derived Shh targets interstitial fibroblasts. A–C, Representative micrographs of immunohistochemical staining show marked induction of Shh protein after renal ischemia reperfusion injury (IRI) at 1 (B) and 10 days (C), respectively. Shh is barely detectable in sham control (A). At 1 day after IRI, Shh expression was significantly induced (B, red arrowhead) in renal tubules. At 10 days, sustained activation of Shh in renal tubules was observed (C, red arrowhead). D, Identification of the interstitial fibroblasts as Shh-responsive cells in fibrotic kidneys. Transgenic Gli1-CreERT2 mice were subjected to IRI for 10 days, and kidneys subjected to double immunostaining for Cre recombinase (red) and various cell type-specific markers (green). Wide arrows indicate cells with positive staining for both vimentin and Cre; arrowheads denote Cre-positive cells; arrows show CD45- or CD31-positive cells. Panel D was reproduced from our published paper (Zhou et al., 2014) with permission. E, Schematic diagram shows that Shh mediates epithelial-mesenchymal communication between injured tubules and interstitial fibroblasts, leading to fibroblast activation and proliferation, as well as matrix overproduction.
Figure 3
Figure 3
Therapeutic strategies to target Shh signaling pathway. The Shh signaling could be blocked at different levels, including Shh ligand inhibitors, Smo receptor inhibitors and transcriptional factors Gli inhibitors. Among these antagonists, Smo inhibitors (cyclopamine and IPI-926) and Gli inhibitors (Darinaparsin and GANT61) are tested in the setting of fibrotic CKD. Except for IPI-926 (Fabian et al., 2012), all Shh signaling inhibitors are able to attenuate renal fibrosis in experimental models.
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