Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis

Kashyap, Sonu; Hein, Kyaw Zaw; Chini, Claudia C.S.; Lika, Jorgo; Warner, Gina M.; Bale, Laurie K.; Torres, Vicente E.; Harris, Peter C.; Oxvig, Claus; Conover, Cheryl A.; Chini, Eduardo N.

doi:10.1172/jci.insight.135700

Cited by 19 publications

(12 citation statements)

References 94 publications

(116 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Following unilateral nephrectomy, for example, the contralateral kidney shows compensatory growth in an IGF dependent manner ( Rosendahl et al, 1992 ). Renal expression of IGF-1, IGF1 receptor, IGFBP4, IGFBP5, and PAPP-A are all increased in an autosomal dominant polycystic disease (ADPKD) mouse model ( Kashyap et al, 2020 ). A recent study reported that PAPP-A knockout significantly decreased cyst development and improved kidney injury response in the ADPKD mice ( Kashyap et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…Renal expression of IGF-1, IGF1 receptor, IGFBP4, IGFBP5, and PAPP-A are all increased in an autosomal dominant polycystic disease (ADPKD) mouse model ( Kashyap et al, 2020 ). A recent study reported that PAPP-A knockout significantly decreased cyst development and improved kidney injury response in the ADPKD mice ( Kashyap et al, 2020 ). STC1 has been identified as one of the chronic kidney disease genes by genome-wide association studies ( Böger and Heid, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Calcium State-Dependent Regulation of Epithelial Cell Quiescence by Stanniocalcin 1a

Liu

Goldstein

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The molecular mechanisms regulating cell quiescence-proliferation balance are not well defined. Using a zebrafish model, we report that Stc1a, a secreted glycoprotein, plays a key role in regulating the quiescence-proliferation balance of Ca2+ transporting epithelial cells (ionocytes). Zebrafish stc1a, but not the other stc genes, is expressed in a Ca2+ state-dependent manner. Genetic deletion of stc1a, but not stc2b, increased ionocyte proliferation, leading to elevated body Ca2+ levels, cardiac edema, body swelling, and premature death. The increased ionocyte proliferation was accompanied by an increase in the IGF1 receptor-mediated PI3 kinase-Akt-Tor signaling activity in ionocytes. Inhibition of the IGF1 receptor, PI3 kinase, Akt, and Tor signaling reduced ionocyte proliferation and rescued the edema and premature death in stc1a–/– fish, suggesting that Stc1a promotes ionocyte quiescence by suppressing local IGF signaling activity. Mechanistically, Stc1 acts by inhibiting Papp-aa, a zinc metalloproteinase degrading Igfbp5a. Inhibition of Papp-aa proteinase activity restored ionocyte quiescence-proliferation balance. Genetic deletion of papp-aa or its substrate igfbp5a in the stc1a–/– background reduced ionocyte proliferation and rescued the edema and premature death. These findings uncover a novel and Ca2+ state-dependent pathway regulating cell quiescence. Our findings also provide new insights into the importance of ionocyte quiescent-proliferation balance in organismal Ca2+ homeostasis and survival.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Calcium State-Dependent Regulation of Epithelial Cell Quiescence by Stanniocalcin 1a

Liu

Goldstein

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…While global deletion of STC1 in C57BL/6 mice did not cause major abnormalities (Chang et al, 2005), a recent study using humanized ex vivo and in vivo mouse models suggested that mesenchymal stromal cells secrete STC1 to suppress hematopoietic stem cell (HSC) proliferation (Waclawiczek et al, 2020). Another recent study reported that renal expression of STC1, IGF-1, IGF1 receptor, IGFBP5, and PAPP-A are all increased in an autosomal dominant polycystic disease (ADPKD) mouse model (Kashyap et al, 2020a). STC1 knockout significantly decreased cyst development and improved kidney injury in the ADPKD mice (Kashyap et al, 2020a).…”

Section: Discussionmentioning

confidence: 99%

“…Another recent study reported that renal expression of STC1, IGF-1, IGF1 receptor, IGFBP5, and PAPP-A are all increased in an autosomal dominant polycystic disease (ADPKD) mouse model (Kashyap et al, 2020a). STC1 knockout significantly decreased cyst development and improved kidney injury in the ADPKD mice (Kashyap et al, 2020a).…”

Section: Discussionmentioning

confidence: 99%

Stanniocalcin 1a is a Ca²⁺-regulated switch controlling epithelial cell quiescence-proliferation balance and Ca²⁺uptake

Liu

Goldstein

et al. 2020

Preprint

View full text Add to dashboard Cite

The mechanisms governing cell quiescence-proliferation balance are poorly defined. Using a zebrafish model, here we report that Stc1a, a glycoprotein known as a hypocalcemic hormone, not only inhibits epithelial calcium uptake but also functions as a Ca2+-regulated switch controlling epithelial cell quiescence-proliferation balance. Among the 4 stc genes, only the stc1a expression is [Ca2+]-dependent. Genetic deletion of stc1a, but not stc2b, resulted in elevated body Ca2+ contents, ectopic Ca2+ deposit, body swelling, and premature death. Reducing epithelial calcium channel Trpv6-mediated Ca2+ uptake alleviated these phenotypes. Loss of Stc1a also promoted quiescent epithelial cells to re-enter the cell cycle. This action was accompanied by local IGF signaling activation and increased expression in papp-aa, a zinc metalloproteinase degrading Igfbp5a. Genetic deletion of papp-aa or igfbp5a abolished the elevated epithelial cell reactivation in stc1a−/− mutants. Likewise, inhibition of IGF1 receptor, PI3 kinase, Akt, and Tor signaling abolished epithelial cell reactivation. These results reveal that Stc1a plays dual roles in regulating epithelial calcium uptake and cell quiescence-proliferation balance and implicate Trpv6 and Papp-aa-Igfbp5a-IGF signaling in these functions.

show abstract

“…This suggests the mechanisms by which PAPP‐A modulates longevity can be explored in the adult animal without confounding developmental effects and motivated us to focus on adulthood inhibition in this study. Notably, the effects of PAPP‐A inhibition on aging go beyond lifespan extension; PAPP‐A inhibition delays progression of age‐related pathology in multiple tissues (Conover et al, 2010) and age‐related thymic atrophy (Vallejo et al, 2009), reduces fat accumulation on a high‐fat diet (Conover et al, 2013; Tanner et al, 2008), reduces atherosclerotic plaque progression and neointima formation (Conover et al, 2016; Harrington et al, 2007; Resch et al, 2006), limits spontaneous tumorigenesis and tumor progression in xenograft models (Becker et al, 2015; Conover et al, 2010; Heitzeneder et al, 2019; Torres et al, 2019), and slows polycystic kidney disease (Kashyap et al, 2020). However, the mechanisms giving rise to this diverse set of phenotypes, and the cell types affected by PAPP‐A inhibition, remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of longevity regulator PAPP‐A modulates tissue homeostasis via restraint of mesenchymal stromal cells

et al. 2021

View full text Add to dashboard Cite

Pregnancy‐associated plasma protein‐A (PAPP‐A) is a secreted metalloprotease that increases insulin‐like growth factor (IGF) availability by cleaving IGF‐binding proteins. Reduced IGF signaling extends longevity in multiple species, and consistent with this, PAPP‐A deletion extends lifespan and healthspan; however, the mechanism remains unclear. To clarify PAPP‐A’s role, we developed a PAPP‐A neutralizing antibody and treated adult mice with it. Transcriptomic profiling across tissues showed that anti‐PAPP‐A reduced IGF signaling and extracellular matrix (ECM) gene expression system wide. The greatest reduction in IGF signaling occurred in the bone marrow, where we found reduced bone, marrow adiposity, and myelopoiesis. These diverse effects led us to search for unifying mechanisms. We identified mesenchymal stromal cells (MSCs) as the source of PAPP‐A in bone marrow and primary responders to PAPP‐A inhibition. Mice treated with anti‐PAPP‐A had reduced IGF signaling in MSCs and dramatically decreased MSC number. As MSCs are (1) a major source of ECM and the progenitors of ECM‐producing fibroblasts, (2) the originating source of adult bone, (3) regulators of marrow adiposity, and (4) an essential component of the hematopoietic niche, our data suggest that PAPP‐A modulates bone marrow homeostasis by potentiating the number and activity of MSCs. We found that MSC‐like cells are the major source of PAPP‐A in other tissues also, suggesting that reduced MSC‐like cell activity drives the system‐wide reduction in ECM gene expression due to PAPP‐A inhibition. Dysregulated ECM production is associated with aging and drives age‐related diseases, and thus, this may be a mechanism by which PAPP‐A deficiency enhances longevity.

show abstract

Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis

Cited by 19 publications

References 94 publications

Calcium State-Dependent Regulation of Epithelial Cell Quiescence by Stanniocalcin 1a

Calcium State-Dependent Regulation of Epithelial Cell Quiescence by Stanniocalcin 1a

Stanniocalcin 1a is a Ca²⁺-regulated switch controlling epithelial cell quiescence-proliferation balance and Ca²⁺uptake

Inhibition of longevity regulator PAPP‐A modulates tissue homeostasis via restraint of mesenchymal stromal cells

Contact Info

Product

Resources

About

Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis

Cited by 19 publications

References 94 publications

Calcium State-Dependent Regulation of Epithelial Cell Quiescence by Stanniocalcin 1a

Calcium State-Dependent Regulation of Epithelial Cell Quiescence by Stanniocalcin 1a

Stanniocalcin 1a is a Ca2+-regulated switch controlling epithelial cell quiescence-proliferation balance and Ca2+uptake

Inhibition of longevity regulator PAPP‐A modulates tissue homeostasis via restraint of mesenchymal stromal cells

Contact Info

Product

Resources

About

Stanniocalcin 1a is a Ca²⁺-regulated switch controlling epithelial cell quiescence-proliferation balance and Ca²⁺uptake