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

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.

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Apelin and copeptin: Two opposite biomarkers associated with kidney function decline and cyst growth in autosomal dominant polycystic kidney disease

Peptides ◽

10.1016/j.peptides.2013.08.007 ◽

2013 ◽

Vol 49 ◽

pp. 1-8 ◽

Cited By ~ 14

Author(s):

Antonio Lacquaniti ◽

Valeria Chirico ◽

Rosaria Lupica ◽

Antoine Buemi ◽

Saverio Loddo ◽

...

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Kidney Function ◽

Autosomal Dominant ◽

Polycystic Kidney ◽

Autosomal Dominant Polycystic Kidney ◽

Kidney Function Decline ◽

Cyst Growth

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A study of sirolimus and mTOR kinase inhibitor in a hypomorphic Pkd1 mouse model of autosomal dominant polycystic kidney disease

AJP Renal Physiology ◽

10.1152/ajprenal.00051.2019 ◽

2019 ◽

Vol 317 (1) ◽

pp. F187-F196 ◽

Cited By ~ 6

Author(s):

Sara J. Holditch ◽

Carolyn N. Brown ◽

Daniel J. Atwood ◽

Andrew M. Lombardi ◽

Khoa N. Nguyen ◽

...

Keyword(s):

Kidney Disease ◽

Mouse Model ◽

Polycystic Kidney Disease ◽

Kidney Function ◽

Autosomal Dominant ◽

Kinase Inhibitor ◽

Polycystic Kidney ◽

Mtor Kinase ◽

Autosomal Dominant Polycystic Kidney ◽

Cyst Growth

Autosomal dominant polycystic kidney disease (PKD) is characterized by cyst formation and growth, which are partially driven by abnormal proliferation of tubular cells. Proproliferative mechanistic target of rapamycin (mTOR) complexes 1 and 2 (mTORC1 and mTORC2) are activated in the kidneys of mice with PKD. Sirolimus indirectly inhibits mTORC1. Novel mTOR kinase inhibitors directly inhibit mTOR kinase, resulting in the inhibition of mTORC1 and mTORC2. The aim of the present study was to determine the effects of sirolimus versus the mTOR kinase inhibitor torin2 on cyst growth and kidney function in the Pkd1 p.R3277C ( Pkd1RC/RC) mouse model, a hypomorphic Pkd1 model orthologous to the human condition, and to determine the effects of sirolimus versus torin2 on mTORC1 and mTORC2 signaling in PKD1−/− cells and in the kidneys of Pkd1RC/RC mice. In vitro, both inhibitors reduced mTORC1 and mTORC2 phosphorylated substrates and negatively impacted cellular metabolic activity, as measured by MTT assay. Pkd1RC/RC mice were treated with sirolimus or torin2 from 50 to 120 days of age. Torin2 was as effective as sirolimus in decreasing cyst growth and improving loss of kidney function. Both sirolimus and torin2 decreased phosphorylated S6 protein, phosphorylated eukaryotic translation initiation factor 4E-binding protein 1, phosphorylated Akt, and proliferation in Pkd1RC/RC kidneys. In conclusion, torin2 and sirolimus were equally effective in decreasing cyst burden and improving kidney function and mediated comparable effects on mTORC1 and mTORC2 signaling and proliferation in the Pkd1RC/RC kidney.

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Complications of Polycystic Kidney Disease and Relation With Disease Progression: An Observational Retrospective Study

10.21203/rs.3.rs-122413/v1 ◽

2020 ◽

Author(s):

Mònica Pérez-Mir ◽

Laura Carreras-Planella ◽

Francesc Borràs ◽

Josep Bonet ◽

Maribel Troya

Keyword(s):

Blood Pressure ◽

Renal Function ◽

Retrospective Study ◽

Kidney Disease ◽

Polycystic Kidney Disease ◽

Kidney Function ◽

High Blood Pressure ◽

Inherited Disease ◽

Polycystic Kidney ◽

Renal Complication

Abstract Background: Autosomal dominant polycystic kidney disease (ADPKD) is a renal inherited disease characterized by the growth of bilateral renal cysts that lead to deterioration in renal function and end-stage renal disease (ESRD). These patients frequently present complications like urinary tract infection, acute pyelonephritis, acute or chronic pain, renal lithiasis or high blood pressure (HBP). The aim of this study is to compare the renal evolution in ADPKD patients with renal complications and/or HBP compared to those without complications nor HBP.Methods: Observational retrospective study of 29 ADPKD patients with normal renal function and <70 years followed up in our center. Clinical and analytical information of 2010, 2015 and 2017 were determined.Results: 29 patients were enrolled with a median age of 41 years [34-54], eighteen women (62,1%) and eleven men. Median of estimation of glomerular function rate (eGFR) was 85.8ml/min [70.7-115.6] in 2010, 76.0 ml/min [57.0-99.9] in 2015 and 63.1ml/min [45.0-95.8] in 2017. Eight patients (27.6%) have never had kidney complication nor HBP. Nine patients (31.0%) have normal blood pressure, 6 others (20.7%) have well controlled high blood pressure (HBP) and 14 (48.3%) have badly controlled HBP. When patients were divided between those who have never presented a complication (C-) and those who present renal complication and/or HBP (C+), the first group presented better kidney function. When patients were segregated into those who have never presented complication or well-controlled HBP (CHBP-) and those with renal complication and/or badly-controlled HBP (CHBP+) no differences were found at the initial eGFR, but a faster worsening of kidney function in CHBP+ group.Conclusions: In ADPKD patients, the decrease in eGFR is significantly important in individuals showing complications (including HBP) compared to those who did not present complications. Individuals with complications and badly-controlled HBP show even greater differences in kidney function decrease compared with patients without complications or well controlled HBP.

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Serum Fas Ligand, Serum Myostatin and Urine TGF-β1 Are Elevated in Autosomal Dominant Polycystic Kidney Disease Patients with Impaired and Preserved Renal Function

Kidney & Blood Pressure Research ◽

10.1159/000489911 ◽

2018 ◽

Vol 43 (3) ◽

pp. 744-754 ◽

Cited By ~ 6

Author(s):

Vassilios Raptis ◽

Constantinos Bakogiannis ◽

Charalampos Loutradis ◽

Afroditi K. Boutou ◽

Athanasios Sioulis ◽

...

Keyword(s):

Renal Function ◽

Kidney Disease ◽

Polycystic Kidney Disease ◽

Fas Ligand ◽

Autosomal Dominant ◽

Polycystic Kidney ◽

Autosomal Dominant Polycystic Kidney ◽

Tgf Β1

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Everolimus Retards Cyst Growth and Preserves Kidney Function in a Rodent Model for Polycystic Kidney Disease

Kidney & Blood Pressure Research ◽

10.1159/000104818 ◽

2007 ◽

Vol 30 (4) ◽

pp. 253-259 ◽

Cited By ~ 77

Author(s):

Ming Wu ◽

Patricia R. Wahl ◽

Michel Le Hir ◽

Ying Wäckerle-Men ◽

Rudolf P. Wüthrich ◽

...

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Kidney Function ◽

Rodent Model ◽

Polycystic Kidney ◽

Cyst Growth

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Discoidan Domain Receptor 1 (DDR1) Tyrosine Kinase is Upregulated in PKD Kidneys But Does Not Play a Role in the Pathogenesis of Polycystic Kidney Disease

10.1101/527614 ◽

2019 ◽

Author(s):

Edward Y Skolnik ◽

Irfana Soomro ◽

Aram Hong ◽

Zhai Li ◽

James Duncan ◽

...

Keyword(s):

Kidney Disease ◽

Tyrosine Kinase ◽

Polycystic Kidney Disease ◽

Kidney Function ◽

Cancer Progression ◽

Drug Targets ◽

Therapeutic Drug ◽

Polycystic Kidney ◽

Cyst Growth

Tolvaptan is the only drug approved to slow cyst growth and preserve kidney function in patients with autosomal dominant polycystic kidney disease (ADPKD). However, its limited efficacy combined with significant side effects underscores the need to identify new and safe therapeutic drug targets to slow progression to end stage kidney disease. We identified DDR1 as receptor tyrosine kinase upregulated in vivo in 3 mouse models of ADPKD using a novel mass spectrometry approach to identify kinases upregulated in ADPKD. Previous studies demonstrating critical roles for DDR1 to cancer progression, its potential role in the pathogenesis of a variety of other kidney disease, along with the possibility that DDR1 could provide new insight into how extracellular matrix impacts cyst growth led us to study the role of DDR1 in ADPKD pathogenesis. However, genetic deletion of DDR1 using CRISPR/Cas9 failed to slow cyst growth or preserve kidney function in both a rapid and slow mouse model of ADPKD demonstrating that DDR1 does not play a role in PKD pathogenesis and is thus a not viable drug target. In spite of the negative results, our studies will be of interest to the nephrology community as it will prevent others from potentially conducting similar experiments on DDR1 and reinforces the potential of performing unbiased screens coupled with in vivo gene editing using CRISPR/Cas9 to rapidly identify and confirm new potential drug targets for ADPKD.

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

AJP Renal Physiology ◽

10.1152/ajprenal.00246.2018 ◽

2018 ◽

Vol 315 (6) ◽

pp. F1695-F1707 ◽

Cited By ~ 7

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.

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