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

2018 ◽  
Vol 315 (6) ◽  
pp. F1695-F1707 ◽  
Author(s):  
Archana Raman ◽  
Stephen C. Parnell ◽  
Yan Zhang ◽  
Gail A. Reif ◽  
Yuqiao Dai ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Renal Function ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Tissue Repair ◽  
Rho Gtpase ◽  
Type I ◽  
Polycystic Kidney ◽  
Collecting Ducts ◽  
Cyst Growth

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.

scholarly journals The Lonidamine Derivative H2-Gamendazole Reduces Cyst Formation in Polycystic Kidney Disease

2020 ◽  
Author(s):  
Shirin V. Sundar ◽  
Xia Zhou ◽  
Brenda S. Magenheimer ◽  
Gail A. Reif ◽  
Darren P. Wallace ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Kidney Disease ◽  
Cell Motility ◽  
Polycystic Kidney Disease ◽  
Short Circuit ◽  
Cyst Formation ◽  
Polycystic Kidney ◽  
Cyst Growth

ABSTRACTAutosomal dominant polycystic kidney disease (ADPKD) is a debilitating renal neoplastic disorder with limited treatment options. It is characterized by the formation of large fluid-filled cysts that develop from kidney tubules through abnormal cell proliferation and cyst-filling fluid secretion driven by cAMP-dependent Cl− secretion. We have examined the effectiveness of the indazole carboxylic acid, H2-gamendazole (H2-GMZ), a derivative of lonidamine, to inhibit these processes and cyst formation using in vitro and in vivo models of ADPKD. H2-GMZ was effective in rapidly blocking forskolin-induced, Cl−-mediated short-circuit currents in human ADPKD cells at 1 μM and it significantly inhibited both cAMP- and EGF-induced proliferation of ADPKD cells with an IC50 of 5-10 μM. Western blot analysis of H2-GMZ-treated ADPKD cells showed decreased phosphorylated ERK and hyperphosphorylated Rb levels. H2-GMZ treatment also decreased ErbB2, Akt, and Cdk4, consistent with inhibition of the chaperone Hsp90, and reduced the levels of the CFTR Cl− channel. H2-GMZ-treated ADPKD cultures contained a higher proportion of smaller cells with fewer and smaller lamellipodia and decreased cytoplasmic actin staining, and they were unable to accomplish wound closure even at low H2-GMZ concentrations, consistent with an alteration in the actin cytoskeleton and decreased cell motility. Studies using mouse metanephric organ cultures showed that H2-GMZ inhibited cAMP-stimulated cyst growth and enlargement. In vivo, H2-GMZ (20mg/kg) was effective in slowing postnatal cyst formation and kidney enlargement in the Pkd1flox/flox:Pkhd1-Cre mouse model. Thus, H2-GMZ treatment decreases Cl− secretion, cell proliferation, cell motility, and cyst growth. These properties, along with its reported low toxicity, suggest that H2-GMZ might be an attractive candidate for treatment of ADPKD.

scholarly journals Cyclin-Dependent Kinase 1 Activity Is a Driver of Cyst Growth in Polycystic Kidney Disease

2020 ◽  
Vol 32 (1) ◽  
pp. 41-51
Author(s):  
Chao Zhang ◽  
Bruno Balbo ◽  
Ming Ma ◽  
Jun Zhao ◽  
Xin Tian ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Effective Means ◽  
Central Component ◽  
Polycystic Kidney ◽  
Double Knockout ◽  
Cyst Cell ◽  
Cyst Growth

BackgroundMutations in PKD1 and PKD2, which encode the transmembrane proteins polycystin-1 and polycystin-2, respectively, cause autosomal dominant polycystic kidney disease (ADPKD). Polycystins are expressed in the primary cilium, and disrupting cilia structure significantly slows ADPKD progression following inactivation of polycystins. The cellular mechanisms of polycystin- and cilia-dependent cyst progression in ADPKD remain incompletely understood.MethodsUnbiased transcriptional profiling in an adult-onset Pkd2 mouse model before cysts formed revealed significant differentially expressed genes (DEGs) in Pkd2 single-knockout kidneys, which were used to identify candidate pathways dysregulated in kidneys destined to form cysts. In vivo studies validated the role of the candidate pathway in the progression of ADPKD. Wild-type and Pkd2/Ift88 double-knockout mice that are protected from cyst growth served as controls.ResultsThe RNASeq data identified cell proliferation as the most dysregulated pathway, with 15 of 241 DEGs related to cell cycle functions. Cdk1 appeared as a central component in this analysis. Cdk1 expression was similarly dysregulated in Pkd1 models of ADPKD, and conditional inactivation of Cdk1 with Pkd1 markedly improved the cystic phenotype and kidney function compared with inactivation of Pkd1 alone. The Pkd1/Cdk1 double knockout blocked cyst cell proliferation that otherwise accompanied Pkd1 inactivation alone.ConclusionsDysregulation of Cdk1 is an early driver of cyst cell proliferation in ADPKD due to Pkd1 inactivation. Selective targeting of cyst cell proliferation is an effective means of slowing ADPKD progression caused by inactivation of Pkd1.

scholarly journals Cux1 promotes cell proliferation and polycystic kidney disease progression in an ADPKD mouse model

2017 ◽  
Vol 313 (4) ◽  
pp. F1050-F1059 ◽  
Author(s):  
Binu Porath ◽  
Safia Livingston ◽  
Erica L. Andres ◽  
Alexandra M. Petrie ◽  
Joshua C. Wright ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Kidney Disease ◽  
Mouse Model ◽  
Polycystic Kidney Disease ◽  
Kidney Development ◽  
Kinase Inhibitor ◽  
Regulatory Gene ◽  
Cyst Formation ◽  
Polycystic Kidney ◽  
Collecting Ducts

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenic hereditary disorders in humans characterized by fluid-filled cysts, primarily in the kidneys. Cux1, a cell cycle regulatory gene highly expressed during kidney development, is elevated in the cyst-lining cells of Pkd1 mutant mice, and in human ADPKD cells. However, forced expression of Cux1 is insufficient to induce cystic disease in transgenic mice or to induce rapid cyst formation after cilia disruption in the kidneys of adult mice. Here we report a double mutant mouse model that has a conditional deletion of the Pkd1 gene in the renal collecting ducts together with a targeted mutation in the Cux1 gene (Pkd1CD;Cux1tm2Ejn). While kidneys isolated from newborn Pkd1CD mice exhibit cortical and medullary cysts, kidneys isolated from newborn Pkd1CD;Cux1tm2Ejn−/− mice did not show any cysts. Because Cux1tm2Ejn−/− are perinatal lethal, we evaluated Pkd1CD mice that were heterozygote for the Cux1 mutation. Similar to the newborn Pkd1CD;Cux1tm2Ejn−/− mice, newborn Pkd1CD;Cux1tm2Ejn+/− mice did not show any cysts. Comparison of Pkd1CD and Pkd1CD;Cux1tm2Ejn+/− mice at later stages of development showed a reduction in the severity of PKD in the Pkd1CD;Cux1tm2Ejn+/− mice. Moreover, we observed an increase in expression of the cyclin kinase inhibitor p27, a target of Cux1 repression, in the rescued collecting ducts. Taken together, our results suggest that Cux1 expression in PKD is not directly involved in cystogenesis but promotes cell proliferation required for expansion of existing cysts, primarily by repression of p27.

TWEAK Signaling Pathway Blockade Slows Cyst Growth and Disease Progression in Autosomal Dominant Polycystic Kidney Disease

2021 ◽  
pp. ASN.2020071094
Author(s):  
Adrian Cordido ◽  
Laura Nuñez-Gonzalez ◽  
Julio Martinez-Moreno ◽  
Olaya Lamas-Gonzalez ◽  
Laura Rodriguez-Osorio ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Kidney Disease ◽  
Signaling Pathway ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Cystic Disease ◽  
Polycystic Kidney ◽  
Pathway Activation ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

Background: In autosomal dominant polycystic kidney disease (ADPKD), cyst development and enlargement lead to end-stage kidney disease. Macrophage recruitment and interstitial inflammation have been shown to promote cyst growth. TWEAK is a TNF superfamily (TNFSF) cytokine that regulates inflammatory responses, cell proliferation and cell death, and its receptor Fn14 (TNFRSF12a) is expressed in macrophage and nephron epithelia. Methods: In order to evaluate the role of the TWEAK signaling pathway in cystic disease, we evaluated Fn14 expression in human and in an orthologous murine model of ADPKD. We also explored the cystic response to TWEAK signaling pathway activation and inhibition by peritoneal injection. Results: Meta-analysis of published animal models data of cystic disease reveals mRNA upregulation of several components of the TWEAK signaling pathway. We also observed that TWEAK and Fn14 were overexpressed in mouse ADPKD kidney cysts, while TWEAK was significantly high in urine and cystic fluid from ADPKD patients. TWEAK administration induced cystogenesis and increased cystic growth, worsening the phenotype in a murine ADPKD model. Anti-TWEAK antibodies significantly slowed the progression of ADPKD, preserved renal function, and improved survival. Furthermore, the anti-TWEAK cystogenesis reduction is related to decreased cell proliferation-MAPK signaling, decreased NF-κB pathway activation, slight reduction of fibrosis and apoptosis, and an indirect decrease of macrophage recruitment. Conclusions: This study identifies the TWEAK signaling pathway as a new disease mechanism involved in cystogenesis and cystic growth and may lead to a new therapeutic approach in ADPKD.

Restoring multidrug resistance-associated protein 3 attenuates cell proliferation in the polycystic kidney

2015 ◽  
Vol 308 (9) ◽  
pp. F1004-F1011 ◽  
Author(s):  
EunSun Chang ◽  
Eun Young Park ◽  
Yu mi Woo ◽  
Duk-Hee Kang ◽  
Young-Hwan Hwang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Renal Function ◽  
Multidrug Resistance ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Drug Targets ◽  
Cyst Formation ◽  
Polycystic Kidney ◽  
Renal Epithelial Cell

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by abnormal proliferation of renal tubular epithelial cells, resulting in the loss of renal function. Despite identification of the genes responsible for ADPKD, few effective drugs are currently available for the disease. Thus finding additional effective drug targets is necessary. The functions of multidrug- resistance-associated protein 3 (MRP3) have been reported only in the field of drug resistance, and the renal functions of MRP3 are mostly unknown. In this study, we found that MRP3 was significantly downregulated in kidneys of human patients with ADPKD and polycystic kidney disease (PKD) mouse models. Our results suggest that downregulated MRP3 stimulated renal epithelial cell proliferation through the B-Raf/MEK/ERK signaling pathway. In contrast, we found that restoring MRP3 reduced cell proliferation and cystogenesis in vitro. These results suggest that the renal function of MRP3 is related to renal cell proliferation and cyst formation and that restoring MRP3 may be an effective therapeutic approach for PKD.

Steviol retards renal cyst growth through reduction of CFTR expression and inhibition of epithelial cell proliferation in a mouse model of polycystic kidney disease

2014 ◽  
Vol 88 (3) ◽  
pp. 412-421 ◽  
Author(s):  
Chaowalit Yuajit ◽  
Chatchai Muanprasat ◽  
Anna-Rachel Gallagher ◽  
Sorin V. Fedeles ◽  
Suticha Kittayaruksakul ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Kidney Disease ◽  
Epithelial Cell ◽  
Mouse Model ◽  
Polycystic Kidney Disease ◽  
Renal Cyst ◽  
Epithelial Cell Proliferation ◽  
Polycystic Kidney ◽  
Cyst Growth

scholarly journals Overexpression of TGF-β1 induces renal fibrosis and accelerates the decline in kidney function in polycystic kidney disease

2020 ◽  
Vol 319 (6) ◽  
pp. F1135-F1148
Author(s):  
Yan Zhang ◽  
Yuqiao Dai ◽  
Archana Raman ◽  
Emily Daniel ◽  
July Metcalf ◽  
...  
Keyword(s):  
Renal Function ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Kidney Function ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Combined Therapy ◽  
Polycystic Kidney ◽  
Tgf Β1 ◽  
Cyst Growth

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the presence of numerous fluid-filled cysts, extensive fibrosis, and the progressive decline in kidney function. Transforming growth factor-β1 (TGF-β1), an important mediator for renal fibrosis and chronic kidney disease, is overexpressed by cystic cells compared with normal kidney cells; however, its role in PKD pathogenesis remains undefined. To investigate the effect of TGF-β1 on cyst growth, fibrosis, and disease progression, we overexpressed active TGF-β1 specifically in collecting ducts (CDs) of phenotypic normal ( Pkd1RC/+) and Pkd1RC/RC mice. In normal mice, CD-specific TGF-β1 overexpression caused tubule dilations by 5 wk of age that were accompanied by increased levels of phosphorylated SMAD3, α-smooth muscle actin, vimentin, and periostin; however, it did not induce overt cyst formation by 20 wk. In Pkd1RC/RC mice, CD overexpression of TGF-β1 increased cyst epithelial cell proliferation. However, extensive fibrosis limited cyst enlargement and caused contraction of the kidneys, leading to a loss of renal function and a shortened lifespan of the mice. These data demonstrate that TGF-β1-induced fibrosis constrains cyst growth and kidney enlargement and accelerates the decline of renal function, supporting the hypothesis that a combined therapy that inhibits renal cyst growth and fibrosis will be required to effectively treat ADPKD.

scholarly journals Macrophage migration inhibitory factor is regulated by HIF-1α and cAMP and promotes renal cyst cell proliferation in a macrophage-independent manner

2020 ◽  
Vol 98 (11) ◽  
pp. 1547-1559
Author(s):  
Wajima Safi ◽  
Andre Kraus ◽  
Steffen Grampp ◽  
Johannes Schödel ◽  
Bjoern Buchholz
Keyword(s):  
Cell Proliferation ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Macrophage Migration Inhibitory Factor ◽  
Macrophage Migration ◽  
Polycystic Kidney ◽  
Tubular Cells ◽  
Cyst Lining ◽  
Cyst Growth

Abstract Progressive cyst growth leads to decline of renal function in polycystic kidney disease. Macrophage migration inhibitory factor (MIF) was found to be upregulated in cyst-lining cells in a mouse model of polycystic kidney disease and to promote cyst growth. In addition, MIF can be secreted by tubular cells and may contribute to cyst growth in an autocrine manner. However, the underlying mechanisms leading to induction of MIF in cyst-lining cells remained elusive. Here, we demonstrate that hypoxia-inducible transcription factor (HIF) 1α upregulates MIF in cyst-lining cells in a tubule-specific PKD1 knockout mouse. Pharmacological stabilization of HIF-1α resulted in significant increase of MIF in cyst epithelial cells whereas tubule-specific knockout of HIF-1α prevented MIF upregulation. Identical regulation could be found for ABCA1, which has been shown to act as a transport protein for MIF. Furthermore, we show that MIF and ABCA1 are direct target genes of HIF-1α in human primary tubular cells. Next to HIF-1α and hypoxia, we found MIF being additionally regulated by cAMP which is a strong promotor of cyst growth. In line with these findings, HIF-1α- and cAMP-dependent in vitro cyst growth could be decreased by the MIF-inhibitor ISO-1 which resulted in reduced cyst cell proliferation. In conclusion, HIF-1α and cAMP regulate MIF in primary tubular cells and cyst-lining epithelial cells, and MIF promotes cyst growth in the absence of macrophages. In line with these findings, the MIF inhibitor ISO-1 attenuates HIF-1α- and cAMP-dependent in vitro cyst enlargement. Key messages • MIF is upregulated in cyst-lining cells in a polycystic kidney disease mouse model. • MIF upregulation is mediated by hypoxia-inducible transcription factor (HIF) 1α. • ABCA1, transport protein for MIF, is also regulated by HIF-1α in vitro and in vivo. • MIF is additionally regulated by cAMP, a strong promotor of cyst growth. • MIF-inhibitor ISO-1 reduces HIF-1α- and cAMP-dependent cyst growth.

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