Sonic hedgehog signaling in kidney fibrosis: a master communicator

Zhou, Dong; Tan, Roderick J.; Liu, Youhua

doi:10.1007/s11427-016-0020-y

Cited by 45 publications

(36 citation statements)

References 84 publications

(133 reference statements)

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“…To explore how fibroblasts become activated rapidly after injury, we sought to identify the trigger responsible for fibroblast activation after IRI. To this end, we studied the potential involvement of Shh because earlier studies implicate it as a tubule‐derived growth factor for interstitial fibroblasts in chronic kidney disease (CKD) (25, 33, 34). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Early activation of fibroblasts is required for kidney repair and regeneration after injury

Zhou

Liu

et al. 2019

FASEB j.

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Acute kidney injury (AKI) is a devastating condition with high morbidity and mortality. AKI is characterized by tubular injury, inflammation, and vascular impairment. However, the role of interstitial fibroblasts in the pathogenesis of AKI is largely unknown. Here, we show that fibroblasts were activated, as defined by vimentin expression, at 1 h after AKI triggered by ischemia‐reperfusion injury (IRI). They rapidly entered the cell cycle with Ki‐67‐positive staining, which started at 1 h and peaked at 12 h after IRI, whereas tubular cell proliferation peaked at 3 d. The trigger for such an early activation of fibroblasts was identified as sonic hedgehog (Shh), which was rapidly induced in renal tubules and could target interstitial fibroblasts. Tubule‐specific knockout of Shh in mice inhibited fibroblast activation and aggravated kidney injury and functional decline after IRI. Likewise, pharmacologic inhibition of Shh signaling with cyclopamine also hindered fibroblast activation and exacerbated kidney damage. These studies uncover that tubule‐derived Shh triggers the early activation of fibroblasts, which is required for kidney repair and regeneration. Our findings for the first time illustrate a previously unrecognized importance of interstitial fibroblasts in conferring renal protection in AKI.—Zhou, D., Fu, H., Liu, S., Zhang L., Xiao, L., Bastacky, S. I., Liu, Y. Early activation of fibroblasts is required for kidney repair and regeneration after injury. FASEB J. 33, 12576–12587 (2019). http://www.fasebj.org

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Section: Resultsmentioning

confidence: 99%

Early activation of fibroblasts is required for kidney repair and regeneration after injury

Zhou

Liu

et al. 2019

FASEB j.

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“…Fig 1a–b). Hh ligands, including Sonic hedgehog (Shh) and Indian hedgehog (Ihh), signal by binding to their transmembrane receptor patched (Ptch1) [13], which activates intracellular transcription factors called Gli proteins [14]. These transcription factors include Gli1, Gli2 and Gli3.…”

Section: Tubulointerstitial Fibrosis and Signalingmentioning

confidence: 99%

Fibrotic Changes Mediating Acute Kidney Injury to Chronic Kidney Disease Transition

hAinmhire

Humphreys²

2017

Nephron

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End-stage renal disease (ESRD) is common, costly, and it results from progressive chronic kidney disease (CKD). ESRD claims many lives every year. It is increasingly recognized that episodes of acute kidney injury (AKI) predispose to the future development of CKD and ESRD. While our understanding of the pathophysiology of the AKI to CKD transition is improving, there are no validated therapeutic strategies to prevent this transition. In this review, we summarize the recent progress made in defining the cellular and molecular events underlying the AKI to CKD transition and highlight potential therapeutic targets and strategies to reduce the incidence of CKD following AKI.

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“…Cell-to-cell communication is well known to play a crucial role in guiding the proper development of multicellular organisms during the embryonic stage and in the maintenance of tissue homeostasis in adults under normal physiologic conditions. [12][13][14][15] Such a communication is often achieved through the engagement between secreted soluble cues from a particular cell and the neighboring responding cells via both autocrine and paracrine fashions. Earlier studies have shown that sonic hedgehog (Shh) and Wnt ligands are upregulated in diseased kidneys and could play a role in mediating fibroblast activation in the pathogenesis of CKD.…”

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Tubule-Derived Wnts Are Required for Fibroblast Activation and Kidney Fibrosis

Zhou

Zhang

et al. 2017

JASN

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Cell-cell communication Wnt ligands is necessary in regulating embryonic development and has been implicated in CKD. Because Wnt ligands are ubiquitously expressed, the exact cellular source of the Wnts involved in CKD remains undefined. To address this issue, we generated two conditional knockout mouse lines in which Wntless (Wls), a dedicated cargo receptor that is obligatory for Wnt secretion, was selectively ablated in tubular epithelial cells or interstitial fibroblasts. Blockade of Wnt secretion by genetic deletion of Wls in renal tubules markedly inhibited myofibroblast activation and reduced renal fibrosis after unilateral ureteral obstruction. This effect associated with decreased activation of-catenin and downstream gene expression and preserved tubular epithelial integrity. In contrast, fibroblast-specific deletion of Wls exhibited little effect on the severity of renal fibrosis after obstructive or ischemia-reperfusion injury. , incubation of normal rat kidney fibroblasts with tubule-derived Wnts promoted fibroblast proliferation and activation. Furthermore, compared with kidney specimens from patients without CKD, biopsy specimens from patients with CKD also displayed increased expression of multiple Wnt proteins, predominantly in renal tubular epithelium. These results illustrate that tubule-derived Wnts have an essential role in promoting fibroblast activation and kidney fibrosis epithelial-mesenchymal communication.

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Sonic hedgehog signaling in kidney fibrosis: a master communicator

Cited by 45 publications

References 84 publications

Early activation of fibroblasts is required for kidney repair and regeneration after injury

Early activation of fibroblasts is required for kidney repair and regeneration after injury

Fibrotic Changes Mediating Acute Kidney Injury to Chronic Kidney Disease Transition

Tubule-Derived Wnts Are Required for Fibroblast Activation and Kidney Fibrosis

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