Hedgehog signaling indirectly affects tubular cell survival after obstructive kidney injury

Rauhauser, Alysha; Ren, Cheng; Lu, Dongmei; Li, Binghua; Zhu, Jili; McEnery, Kayla; Vadnagara, Komal; Zepeda‐Orozco, Diana; Zhou, Xin; Lin, Fangming; Jetten, Anton M.; Attanasio, Massimo

doi:10.1152/ajprenal.00232.2015

Cited by 30 publications

(35 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although the damaged tubular cells may undergo a variety of maladaptive changes such as partial epithelial-mesenchymal transition (EMT), cell cycle arrest, defects in cell metabolism (Grande et al, 2015; Kang et al, 2015; Liu, 2010; Lovisa et al, 2015), one common consequence of these diverse responses is converting to a secretory phenotype (Zhou and Liu, 2016). Indeed, marked induction of Shh protein is observed in the fibrotic kidneys in all commonly used CKD models, including folic acid (FA), unilateral ureteral obstruction (UUO), ischemia reperfusion injury (IRI), adriamycin (ADR) and 5/6 nephrectomy, although it is barely detectable in normal kidneys (Ding et al, 2012; Fabian et al, 2012; Rauhauser et al, 2015; Zhou et al, 2014). In human biopsy specimens, Shh is also specifically induced in renal tubular epithelium of the diseased kidney, regardless of the initial etiologies (Zhou et al, 2014).…”

Section: Shh Signaling and Ckdmentioning

confidence: 99%

“…This conclusion is also supported by genetic and pharmacologic manipulations of the Shh downstream mediators Smo or Gli proteins. It is shown that the kidneys in Gli1-deficient mice are protected against the development of tubulointerstitial fibrosis after UUO (Ding et al, 2012; Rauhauser et al, 2015). Smo inhibitors such as cyclopamine also repress the induction of Gli1, Snail1 and α-SMA, and reduce matrix expression and mitigate fibrotic lesions in obstructive nephropathy (Ding et al, 2012; Rauhauser et al, 2015), although it does not affect renal Shh expression.…”

Section: Shh Signaling and Ckdmentioning

confidence: 99%

“…It is shown that the kidneys in Gli1-deficient mice are protected against the development of tubulointerstitial fibrosis after UUO (Ding et al, 2012; Rauhauser et al, 2015). Smo inhibitors such as cyclopamine also repress the induction of Gli1, Snail1 and α-SMA, and reduce matrix expression and mitigate fibrotic lesions in obstructive nephropathy (Ding et al, 2012; Rauhauser et al, 2015), although it does not affect renal Shh expression. Another study demonstrates that Gli2 in Shh pathway is expressed in myofibroblast progenitors, and drive cell-cycle progression in cultured mesenchymal stem cell-like progenitors (Kramann et al, 2015).…”

Section: Shh Signaling and Ckdmentioning

confidence: 99%

“…Myofibroblast-specific deletion of Gli2 or overexpression of Gli3 repressor attenuates renal fibrosis after UUO (Kramann et al, 2015). In addition, suppression of Shh signaling is also associated with decreased macrophage infiltration after obstructive injury (Rauhauser et al, 2015). …”

Section: Shh Signaling and Ckdmentioning

confidence: 99%

“…There are three hedgehog ligands in mammals: Sonic hedgehog (Shh), Indian hedgehog (Ihh) and Desert hedgehog (Dhh), of which Shh is the best characterized (Lum and Beachy, 2004). Accumulating studies have demonstrated an activated Shh signaling in fibrotic CKD, suggesting a potential connection between aberrant regulation of this signaling and kidney fibrosis (Ding et al, 2012; Fabian et al, 2012; Kramann et al, 2015; Rauhauser et al, 2015; Zhou et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Sonic hedgehog signaling in kidney fibrosis: a master communicator

Zhou

Tan

Liu

2016

Sci. China Life Sci.

View full text Add to dashboard Cite

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.

show abstract

Section: Shh Signaling and Ckdmentioning

confidence: 99%

Section: Shh Signaling and Ckdmentioning

confidence: 99%

Section: Shh Signaling and Ckdmentioning

confidence: 99%

Section: Shh Signaling and Ckdmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Sonic hedgehog signaling in kidney fibrosis: a master communicator

Zhou

Tan

Liu

2016

Sci. China Life Sci.

View full text Add to dashboard Cite

show abstract

GLIS1–3 transcription factors: critical roles in the regulation of multiple physiological processes and diseases

Jetten

2018

Cell. Mol. Life Sci.

Self Cite

View full text Add to dashboard Cite

Krüppel-like zinc finger proteins form one of the largest families of transcription factors. They function as key regulators of embryonic development and a wide range of other physiological processes, and are implicated in a variety of pathologies. GLI-Similar 1–3 (GLIS1–3) constitute a subfamily of Krüppel-like zinc finger proteins that act either as activators or repressors of gene transcription. GLIS3 plays a critical role in the regulation of multiple biological processes and is a key regulator of pancreatic β cell generation and maturation, insulin gene expression, thyroid hormone biosynthesis, spermatogenesis, and the maintenance of normal kidney functions. Loss of GLIS3 function in humans and mice leads to the development of several pathologies, including neonatal diabetes and congenital hypothyroidism, polycystic kidney disease, and infertility. Single nucleotide polymorphisms in GLIS3 genes have been associated with increased risk of several diseases, including type 1 and type 2 diabetes, glaucoma, and neurological disorders. GLIS2 plays a critical role in the kidney and GLIS2 dysfunction leads to nephronophthisis, an end-stage, cystic renal disease. In addition, GLIS1–3 have regulatory functions in several stem/progenitor cell populations. GLIS1 and GLIS3 greatly enhance reprogramming efficiency of somatic cells into induced embryonic stem cells, while GLIS2 inhibits reprogramming. Recent studies have obtained substantial mechanistic insights into several physiological processes regulated by GLIS2 and GLIS3, while little is still known about the physiological functions of GLIS1. The localization of some GLIS proteins to the primary cilium suggests that their activity may be regulated by a downstream primary cilium-associated signaling pathway. Insights into the upstream GLIS signaling pathway may provide opportunities for the development of new therapeutic strategies for diabetes, hypothyroidism, and other diseases.

show abstract