Aberrant expression of laminin-332 promotes cell proliferation and cyst growth in ARPKD

Vijayakumar, Soundarapandian; Dang, Suparna; Marinkovich, M. Peter; Lazarova, Zelmira; Yoder, Bradley K.; Torres, Vincente E; Wallace, Darren P.

doi:10.1152/ajprenal.00104.2013

Cited by 17 publications

(14 citation statements)

References 47 publications

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“…4 Abnormal and extensive expression of ECM molecules, including laminins, collagens, and matricellular proteins, accelerate cyst growth through activation of integrin signaling. 18,19,[61][62][63] Laminin-332 (a 3 , b 3 , g 2 ), also called laminin-5, has been shown to be abnormally expressed in PKD and contributes to cyst epithelial cell proliferation and cyst growth. 61,62 Recently, we discovered that periostin, a tissue repair molecule, was highly overexpressed in ADPKD, autosomal recessive PKD, and animal models of cystic disease.…”

Section: Effect Of Ilk On Cystic Diseasementioning

confidence: 99%

“…18,19,[61][62][63] Laminin-332 (a 3 , b 3 , g 2 ), also called laminin-5, has been shown to be abnormally expressed in PKD and contributes to cyst epithelial cell proliferation and cyst growth. 61,62 Recently, we discovered that periostin, a tissue repair molecule, was highly overexpressed in ADPKD, autosomal recessive PKD, and animal models of cystic disease. 19 Periostin binding to a V -integrins activates mTOR and promotes the proliferation of human ADPKD cells.…”

Section: Effect Of Ilk On Cystic Diseasementioning

confidence: 99%

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Integrin-Linked Kinase Signaling Promotes Cyst Growth and Fibrosis in Polycystic Kidney Disease

Raman

Reif²,

Dai³

et al. 2017

JASN

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Autosomal dominant polycystic kidney disease (ADPKD) is characterized by innumerous fluid-filled cysts and progressive deterioration of renal function. Previously, we showed that periostin, a matricellular protein involved in tissue repair, is markedly overexpressed by cyst epithelial cells. Periostin promotes cell proliferation, cyst growth, interstitial fibrosis, and the decline in renal function in PKD mice. Here, we investigated the regulation of these processes by the integrin-linked kinase (ILK), a scaffold protein that links the extracellular matrix to the actin cytoskeleton and is stimulated by periostin. Pharmacologic inhibition or shRNA knockdown of ILK prevented periostin-induced Akt/mammalian target of rapamycin (mTOR) signaling and ADPKD cell proliferation Homozygous deletion of ILK in renal collecting ducts (CD) of ; mice caused tubule dilations, apoptosis, fibrosis, and organ failure by 10 weeks of age. By contrast, ; mice had normal renal morphology and function and survived >1 year. Reduced expression of ILK in ; mice, a rapidly progressive model of ADPKD, decreased renal Akt/mTOR activity, cell proliferation, cyst growth, and interstitial fibrosis, and significantly improved renal function and animal survival. Additionally, CD-specific knockdown of ILK strikingly reduced renal cystic disease and fibrosis and extended the life of mice, a slowly progressive PKD model. We conclude that ILK is critical for maintaining the CD epithelium and renal function and is a key intermediate for periostin activation of signaling pathways involved in cyst growth and fibrosis in PKD.

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Section: Effect Of Ilk On Cystic Diseasementioning

confidence: 99%

Section: Effect Of Ilk On Cystic Diseasementioning

confidence: 99%

Integrin-Linked Kinase Signaling Promotes Cyst Growth and Fibrosis in Polycystic Kidney Disease

Raman

Reif²,

Dai³

et al. 2017

JASN

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“…Inexorable cyst growth leads to the loss of functional nephrons, inflammation, fibrosis, and decline in kidney function. Elevated expression of extracellular matrix (ECM) components including matricellular proteins, growth factors, surface receptors, and integrins by cystic epithelial cells (37,42,56,62,66,72) is consistent with transcriptional reprogramming observed during tissue repair, which may contribute to disease progression (6, 31, 69 -71).…”

Section: Introductionmentioning

confidence: 77%

Periostin overexpression in collecting ducts accelerates renal cyst growth and fibrosis in polycystic kidney disease

Raman

Parnell

Zhang

et al. 2018

American Journal of Physiology-Renal Physiology

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In polycystic kidney disease (PKD), persistent activation of cell proliferation and matrix production contributes to cyst growth and fibrosis, leading to progressive deterioration of renal function. Previously, we showed that periostin, a matricellular protein involved in tissue repair, is overexpressed by cystic epithelial cells of PKD kidneys. Periostin binds αVβ3-integrins and activates integrin-linked kinase (ILK), leading to Akt/mammalian target of rapamycin (mTOR)-mediated proliferation of human PKD cells. By contrast, periostin does not stimulate the proliferation of normal human kidney cells. This difference in the response to periostin is due to elevated expression of αVβ3-integrins by cystic cells. To determine whether periostin accelerates cyst growth and fibrosis, we generated mice with conditional overexpression of periostin in the collecting ducts (CDs). Ectopic CD expression of periostin was not sufficient to induce cyst formation or fibrosis in wild-type mice. However, periostin overexpression in pcy/pcy ( pcy) kidneys significantly increased mTOR activity, cell proliferation, cyst growth, and interstitial fibrosis; and accelerated the decline in renal function. Moreover, CD-specific overexpression of periostin caused a decrease in the survival of pcy mice. These pathological changes were accompanied by increased renal expression of vimentin, α-smooth muscle actin, and type I collagen. We also found that periostin increased gene expression of pathways involved in repair, including integrin and growth factor signaling and ECM production, and it stimulated focal adhesion kinase, Rho GTPase, cytoskeletal reorganization, and migration of PKD cells. These results suggest that periostin stimulates signaling pathways involved in an abnormal tissue repair process that contributes to cyst growth and fibrosis in PKD.

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“…Tinagl1 would not be the first ECM protein to be associated with ciliopathy-like phenotypes (Zhang et al, 2020). Certain mutants of basement membrane laminin and a knockout of xylosyltransferase 2, an enzyme that initiates glycosaminoglycan synthesis, result in polycystic kidney disease through unknown mechanisms (Condac et al, 2007;Shannon et al, 2006;Vijaykumar et al, 2014). Mutations in the matrix metalloproteinase ADAMTS9 cause nephronophthisis-related ciliopathies in human patients, and endocytosed ADAMTS9 was surprisingly found to be required in periciliary vesicles for an early stage of ciliogenesis (Choi et al, 2019;Nandadasa et al, 2019).…”

Section: Potential Roles Of Tinagl1 In Zebrafish Embryonic Developmentmentioning

confidence: 99%

Acute knockdown of extracellular matrix protein Tinagl1 disrupts heart laterality and pronephric cilia in zebrafish embryonic development

Neiswender

LeMosy

2020

Preprint

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A highly-conserved extracellular matrix protein, Tinagl1, modulates Wnt, integrin, TGF-b, and EGF-R signaling in vitro, but its significance in vivo has remained in doubt. To bypass possible genetic compensation by an ortholog encoded exclusively in mammalian genomes, we examine Tinagl1 function in zebrafish embryos. In this model, tinagl1 mRNA is detected in the developing spinal cord and pronephros. Acute knockdown using either CRISPR/Cas9 somatic mutagenesis or splice-blocking morpholinos reveals left-right (LR) heart looping defects, pronephros dilatations, and ventral body curvature. This constellation of defects characteristically results from the loss of motile cilia function, and we confirm the presence of shortened and fewer cilia in the pronephric duct and in the Kupffer's vesicle where LR asymmetry is established. A link to known Wnt3a/b-catenin signaling that activates the motile cilia transcriptional program is supported by manipulation of Wnt3a and b-catenin levels in tinagl1 knockdown embryos. In addition to ciliopathy-like defects, the tinagl1 knockdown shows disorganization of longitudinal axon tracts in the spinal cord and defects in motor neuron outgrowth. Together, these results provide evidence that Tinagl1 is important in development, and that zebrafish is an ideal model in which to explore its relationships to cilia and secreted signaling molecules.

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Aberrant expression of laminin-332 promotes cell proliferation and cyst growth in ARPKD

Cited by 17 publications

References 47 publications

Integrin-Linked Kinase Signaling Promotes Cyst Growth and Fibrosis in Polycystic Kidney Disease

Integrin-Linked Kinase Signaling Promotes Cyst Growth and Fibrosis in Polycystic Kidney Disease

Periostin overexpression in collecting ducts accelerates renal cyst growth and fibrosis in polycystic kidney disease

Acute knockdown of extracellular matrix protein Tinagl1 disrupts heart laterality and pronephric cilia in zebrafish embryonic development

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