Pyrrolidine dithiocarbamate reduces the progression of total kidney volume and cyst enlargement in experimental polycystic kidney disease

Ta, Michelle H. T.; Rao, Padmashree; Korgaonkar, Mayuresh S.; Foster, Sheryl; Peduto, Anthony; Harris, David C.H.; Rangan, Gopala K.

doi:10.14814/phy2.12196

Cited by 14 publications

(13 citation statements)

References 52 publications

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“…Sections 4–6 microns in thickness were deparaffinised and then either stained by periodic acid-Schiff (PAS), Sirius-red or used in immunohistochemistry. The latter was performed as previously described [ 24 ] using primary antibodies against ED-1 (1:400, MCA341R; Serotec, Kidlington, U.K.), BrdU (1:100, clone MoBu-1, Novus Biologicals, Littleton, CO, USA), Ki-67 (1:100, clone SP6, Lab Vision, CA, USA) and α-SMA (1:4000, A2547; Sigma–Aldrich, St. Louis, MO, USA) to assess for CD68-positive monocytes, cell proliferation (both BrdU and Ki-67) and myofibroblasts/vascular smooth muscle cells respectively.…”

Section: Methodsmentioning

confidence: 99%

“…To determine the effects of sirolimus on TORC1 and TORC2, activation, the expression of downstream targets was assessed by immunohistochemistry using the following primary antibodies: (i) polyclonal anti-rat rabbit phosphorylated S6 ribosomal protein (Ser235/236) (p-S6) (1:150; #2211, Cell Signalling Technology, Danvers, MA, USA); (ii) anti-rat rabbit phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p-4E-BP1) (1:1000; clone 236B4, Cell Signalling Technology, Danvers, MA, USA); (iii) polyclonal rabbit anti-rat phosphorylated Akt (Ser/Thr) (p-Akt) (1:200; #9611, Cell Signalling Technology, Danvers, MA, USA). Immunohistochemistry for p-S6, p-4E-BP1 and p-Akt was performed by antigen retrieval (by 10 minutes of microwave oven heating), overnight incubation with the primary antibody, application of secondary biotinylated antibodies, followed by immunodetection with diaminobenzidine on methylgreen counterstained slides [ 24 ].…”

Section: Methodsmentioning

confidence: 99%

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Effects of TORC1 Inhibition during the Early and Established Phases of Polycystic Kidney Disease

Schwensen

Foster

et al. 2016

PLoS ONE

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The disease-modifying effects of target of rapamycin complex 1 (TORC1) inhibitors during different stages of polycystic kidney disease (PKD) are not well defined. In this study, male Lewis Polycystic Kidney Disease (LPK) rats (a genetic ortholog of human NPHP9, phenotypically characterised by diffuse distal nephron cystic growth) and Lewis controls received either vehicle (V) or sirolimus (S, 0.2 mg/kg by intraperitoneal injection 5 days per week) during the early (postnatal weeks 3 to 10) or late stages of disease (weeks 10 to 20). In early-stage disease, sirolimus reduced kidney enlargement (by 63%), slowed the rate of increase in total kidney volume (TKV) in serial MRI by 78.2% (LPK+V: 132.3±59.7 vs. LPK+S: 28.8±12.0% per week) but only partly reduced the percentage renal cyst area (by 19%) and did not affect the decline in endogenous creatinine clearance (CrCl) in LPK rats. In late-stage disease, sirolimus reduced kidney enlargement (by 22%) and the rate of increase in TKV by 71.8% (LPK+V: 13.1±6.6 vs. LPK+S: 3.7±3.7% per week) but the percentage renal cyst area was unaltered, and the CrCl only marginally better. Sirolimus reduced renal TORC1 activation but not TORC2, NF-κB DNA binding activity, CCL2 or TNFα expression, and abnormalities in cilia ultrastructure, hypertension and cardiac disease were also not improved. Thus, the relative treatment efficacy of TORC1 inhibition on kidney enlargement was consistent at all disease stages, but the absolute effect was determined by the timing of drug initiation. Furthermore, cystic microarchitecture, renal function and cardiac disease remain abnormal with TORC1 inhibition, indicating that additional approaches to normalise cellular dedifferentiation, inflammation and hypertension are required to completely arrest the progression of PKDs.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Effects of TORC1 Inhibition during the Early and Established Phases of Polycystic Kidney Disease

Schwensen

Foster

et al. 2016

PLoS ONE

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“…To assess proteinuria and creatinine clearance (CrCl), rats were placed in metabolic cages for 16 h. Creatinine clearance was calculated using CrCl = [Urine creatinine (µmol/L) × Urine volume (mL/ min)]/Serum creatinine (µmol/L), and was corrected for body weight. Rats were euthanized as previously described [29] .…”

Section: Assessment Of Kidney Enlargement and Renal Function In Lpk Ratsmentioning

confidence: 99%

Constitutive renal Rel/nuclear factor-κB expression in Lewis polycystic kidney disease rats

Schwensen

Liuwantara

et al. 2016

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Author contributions: Schwensen KG conducted the animal study, performed sample collection and histological staining; Ta MHT performed the immunofluorescence, Western blotting, and qPCR experiments, analyzed data and drafted the manuscript; Huso DL and Watnick T developed the Pkd2 knockout mouse model and provided paraffin embedded sections that were utilized for staining; Liuwantara D assisted with data interpretation and provided technical guidance with experimental methods; Rangan GK conceived of the study, conducted the animal study, performed sample collection and histological staining and reviewed and edited the manuscript; all authors read and approved of the final manuscript. Supported by Basic Study(LPK, a genetic ortholog of human nephronopthsis-9) from postnatal weeks 3 to 20. At each timepoint, renal disease progression and the mRNA expression of NF-κB-dependent genes (TNFa and CCL2) were determined. NF-κB was also histologically assessed in human PKD tissue. RESULTS:Progressive kidney enlargement in LPK rats was accompanied by increased renal cell proliferation and interstitial monocyte accumulation (peaking at weeks 3 and 10 respectively), and progressive interstitial fibrosis (with a smooth muscle actin and Sirius Red deposition significantly increased compared to Lewis kidneys from weeks 3 to 6 onwards). Rel/NF-κB proteins (phosphorylated-p105, p65, p50, c-Rel and RelB) were expressed in cystic epithelial cells (CECs) of LPK kidneys as early as postnatal week 3 and sustained until latestage disease at week 20. From weeks 10 to 20, nuclear p65, p50, RelB and cytoplasmic IκBa protein levels, and TNFa and CCL2 expression, were upregulated in LPK compared to Lewis kidneys. NF-κB proteins were consistently expressed in CECs of human PKD. The DNA damage marker γ-H2AX was also identified in the CECs of LPK and human polycystic kidneys. CONCLUSION:Several NF-κB proteins are consistently expressed in CECs in human and experimental PKD. These data suggest that the upregulation of both the canonical and non-canonical pathways of NF-κB signaling may be a constitutive and early pathological feature of cystic renal diseases. Core tip: Until now, there has been limited information regarding the specific nuclear factor (NF)-κB proteins involved in polycystic kidney disease (PKD) and their expression throughout disease progression. Our study demonstrated that a diverse array of NF-κB proteins is expressed in the renal cyst-lining cells of a chronic rodent model of PKD, and that NF-κB expression is constitutive over time. NF-κB was also identified in human PKD, suggesting that NF-κB upregulation is common to renal cystic disease models. Our data suggest that components of both the canonical and non-canonical NF-κB pathway are upregulated in PKD. Future studies should be directed at verifying whether specific NF-κB inhibition can attenuate interstitial inflammation and cyst growth, and slow the decline in renal function in in vivo models of PKD.Ta MHT, Schwensen KG, Liuwantara D, Huso DL, Watnick T, Rangan GK. Con...

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“…TKV also showed a significant correlation, although not as strong as the other two imaging biomarkers. Several previous studies have applied quantitative MRI techniques to the study of kidney disease progression (and response to therapy); however, these studies have focused on genetic models of other forms of PKD, specifically juvenile nephronophthisis (21,22), a disorder that is clinically distinct from ARPKD. Ours is the first study to systematically apply quantitative image analysis of T2W-MRI techniques to assess kidney disease progression and response to therapy in a genetic model of ARPKD.…”

Section: Discussionmentioning

confidence: 99%

“…Quantitative MRI techniques, which can provide reproducible measurements of renal parenchymal changes, are being applied increasingly to the study of chronic kidney diseases (15)(16)(17)(18)(19). Several studies have utilized these techniques to assess kidney disease progression in animal models of polycystic kidney diseases and related "ciliopathies", including juvenile nephronophthisis (20)(21)(22)(23). However, none has utilized quantitative MRI techniques to specifically assess kidney disease progression in an ARPKD model, nor have these techniques been used to measure the treatment effects of a clinically available therapy with the potential to target human ARPKD kidney and liver disease.…”

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confidence: 99%

Quantitative magnetic resonance imaging assessments of autosomal recessive polycystic kidney disease progression and response to therapy in an animal model

et al. 2018

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BackgroundAutosomal recessive polycystic kidney disease (ARPKD) is associated with significant mortality and morbidity, and currently, there are no disease-specific treatments available for ARPKD patients. One major limitation in establishing new therapies for ARPKD is a lack of sensitive measures of kidney disease progression. Magnetic resonance imaging (MRI) can provide multiple quantitative assessments of the disease.MethodsWe applied quantitative image analysis of high-resolution (noncontrast) T2-weighted MRI techniques to study cystic kidney disease progression and response to therapy in the PCK rat model of ARPKD.ResultsSerial imaging over a 2-month period demonstrated that renal cystic burden (RCB, %)=[total cyst volume (TCV)/total kidney volume (TKV) × 100], TCV, and, to a lesser extent, TKV detected cystic kidney disease progression, as well as the therapeutic effect of octreotide, a clinically available medication shown previously to slow both kidney and liver disease progression in this model. All three MRI measures correlated significantly with histologic measures of renal cystic area, although the correlation of RCB and TCV was stronger than that of TKV.ConclusionThese preclinical MRI results provide a basis for applying these quantitative MRI techniques in clinical studies, to stage and measure progression in human ARPKD kidney disease.

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Pyrrolidine dithiocarbamate reduces the progression of total kidney volume and cyst enlargement in experimental polycystic kidney disease

Cited by 14 publications

References 52 publications

Effects of TORC1 Inhibition during the Early and Established Phases of Polycystic Kidney Disease

Effects of TORC1 Inhibition during the Early and Established Phases of Polycystic Kidney Disease

Constitutive renal Rel/nuclear factor-κB expression in Lewis polycystic kidney disease rats

Quantitative magnetic resonance imaging assessments of autosomal recessive polycystic kidney disease progression and response to therapy in an animal model

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