Prioritization of novel ADPKD drug candidates from disease-stage specific gene expression profiles

Malas, Tareq B.; Leonhard, Wouter N.; Bange, Hester; Hettne, Kristina; Price, Leo; Hoen, Peter A C ‘t; Peters, Dorien J.M.

doi:10.1016/j.ebiom.2019.11.046

Cited by 19 publications

(18 citation statements)

References 67 publications

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“…In line with the aforementioned raised concerns, our findings revealed that the selection of appropriate housekeeping genes and consequent use of Ppia as the reference, allowed the detection of differences between groups regarding Stat3 expression, thought to be upregulated in kidney cysts and associated with PKD progression in mouse models 8 , 54 – 60 . On the other hand, the normalization using Gapdh showed no difference.…”

Section: Discussionsupporting

confidence: 69%

Ppia is the most stable housekeeping gene for qRT-PCR normalization in kidneys of three Pkd1-deficient mouse models

Anauate

Amaral

Ferreira

et al. 2021

Sci Rep

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Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited renal disorder, characterized by renal cyst development leading to end-stage renal disease. Although the appropriate choice of suitable reference is critical for quantitative RNA analysis, no comparison of frequently used “housekeeping” genes is available. Here, we determined the validity of 7 candidate housekeeping genes (Actb, Actg1, B2m, Gapdh, Hprt, Pgam1 and Ppia) in kidney tissues from mouse models orthologous to ADPKD, including a cystic mice (CY) 10–12 weeks old (Pkd1flox/flox:Nestincre/Pkd1flox/−:Nestincre, n = 10) and non-cystic (NC) controls (Pkd1flox/flox/Pkd1flox/-, n = 10), Pkd1-haploinsufficient (HT) mice (Pkd1+/−, n = 6) and wild-type (WT) controls (Pkd1+/+, n = 6) and a severely cystic (SC) mice 15 days old (Pkd1V/V, n = 7) and their controls (CO, n = 5). Gene expression data were analyzed using six distinct statistical softwares. The estimation of the ideal number of genes suggested the use of Ppia alone as sufficient, although not ideal, to analyze groups altogether. Actb, Hprt and Ppia expression profiles were correlated in all samples. Ppia was identified as the most stable housekeeping gene, while Gapdh was the least stable for all kidney samples. Stat3 expression level was consistent with upregulation in SC compared to CO when normalized by Ppia expression. In conclusion, present findings identified Ppia as the best housekeeping gene for CY + NC and SC + CO groups, while Hprt was the best for the HT + WT group.

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Section: Discussionsupporting

confidence: 69%

Ppia is the most stable housekeeping gene for qRT-PCR normalization in kidneys of three Pkd1-deficient mouse models

Anauate

Amaral

Ferreira

et al. 2021

Sci Rep

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“…The stage is now set for a Phase 2 parallel-arm multicentre trial of pioglitazone in ADPKD. With no options to slow disease progression in the last 150 years, new treatment possibilities for ADPKD are now rapidly emerging, including drug-repurposing approaches [ 20 , 21 ]: PPAR-γ agonists could yet find a new lease on life in the treatment of ADPKD.…”

Section: Introductionmentioning

confidence: 99%

Drug repurposing in autosomal dominant polycystic kidney disease: back to the future with pioglitazone

Mao

Valluru

Ong

2021

Clinical Kidney Journal

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Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of end-stage kidney failure in man. At present, only one drug, Tolvaptan, has been approved for use in man to slow disease progression but its use is limited by reduced tolerability and idiosyncratic liver toxicity. Thiazolidinediones (TZDs) were first developed as insulin-sensitizers but also regulate gene transcription in multiple tissues leading to systemic effects on metabolism, inflammation and vascular reactivity. In this issue, Blazer-Yost and colleagues report the results of a single centre Phase 1 b double-blind placebo-controlled crossover study of the PPAR-γ agonist, pioglitazone, in 18 ADPKD patients. Encouragingly there were no major safety signals although evidence of efficacy could not be demonstrated due to the small sample size. We review the preclinical evidence for the use of PPAR-γ agonists in ADPKD and speculate on the likely beneficial and adverse clinical effects of this interesting class of compounds in a future trial.

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“…Pioglitazone; a well-known anti-diabetic drug that is a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, has been found to suppress the development of renal cyst in the preclinical studies via different mechanisms which inarguably suggests its pleiotropy. The characteristic property to improve the molecular and phenotypic defects with a lower risk of adverse effects in preclinical animal models has proved pioglitazone an excellent and emerging candidate to treat ADPKD (Liu et al 2020 ; Raphael et al 2009a ; Malas et al 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Autosomal dominant polycystic kidney disease and pioglitazone for its therapy: a comprehensive review with an emphasis on the molecular pathogenesis and pharmacological aspects

Saini¹,

Saini²,

Singh

2020

Mol Med

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Autosomal dominant polycystic kidney disease (ADPKD) is an inherited chronic kidney disorder (CKD) that is characterized by the development of numerous fluid-filled cysts in kidneys. It is caused either due to the mutations in the PKD1 or PKD2 gene that encodes polycystin-1 and polycystin-2, respectively. This condition progresses into end-stage renal disorder if the renal or extra-renal clinical manifestations remain untreated. Several clinical trials with a variety of drugs have failed, and the only Food and Drugs Administration (FDA) approved drug to treat ADPKD to date is tolvaptan that works by antagonizing the vasopressin-2 receptor (V2R). The pathology of ADPKD is complex and involves the malfunction of different signaling pathways like cAMP, Hedgehog, and MAPK/ERK pathway owing to the mutated product that is polycystin-1 or 2. A measured yet substantial number of preclinical studies have found pioglitazone to decrease the cystic burden and improve the renal function in ADPKD. The peroxisome proliferator-activated receptor-gamma is found on the epithelial cells of renal collecting tubule and when it gets agonized by pioglitazone, confers efficacy in ADPKD treatment through multiple mechanisms. There is only one clinical trial (ongoing) wherein it is being assessed for its benefits and risk in patients with ADPKD, and is expected to get approval from the regulatory body owing to its promising therapeutic effects. This article would encompass the updated information on the epidemiology, pathophysiology of ADPKD, different mechanisms of action of pioglitazone in the treatment of ADPKD with preclinical and clinical shreds of evidence, and related safety updates.

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Prioritization of novel ADPKD drug candidates from disease-stage specific gene expression profiles

Cited by 19 publications

References 67 publications

Ppia is the most stable housekeeping gene for qRT-PCR normalization in kidneys of three Pkd1-deficient mouse models

Ppia is the most stable housekeeping gene for qRT-PCR normalization in kidneys of three Pkd1-deficient mouse models

Drug repurposing in autosomal dominant polycystic kidney disease: back to the future with pioglitazone

Autosomal dominant polycystic kidney disease and pioglitazone for its therapy: a comprehensive review with an emphasis on the molecular pathogenesis and pharmacological aspects

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