THE BIOMARKER ENRICHED PROTEOME OF ADULT POLYCYSTIC KIDNEY DISEASE (ADPKD) CYST FLUID
Ontology highlight
ABSTRACT:
INSTRUMENT(S): instrument model, LTQ
ORGANISM(S): Homo Sapiens (human)
SUBMITTER: 
Stephen Mason
PROVIDER: PRD000106 | Pride | 2009-04-30
REPOSITORIES: Pride
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| PRIDE_Exp_Complete_Ac_9286.pride.mztab.gz | Mztab | |||
| PRIDE_Exp_Complete_Ac_9286.xml.gz | Xml |
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Project description:Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by the development of numerous fluid-filled cysts in the kidneys of patients. We recently published our description of the proteome of renal cyst fluid in ADPKD. As a follow-up experiment, we hypothesized that the protein-bound subfraction consists of molecules of mechanistic or diagnostic interest in ADPKD. Using a manual biomarker enrichment kit, we have identified 44 distinct proteins in human cyst fluid.
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Project description:Autosomal dominant polycystic kidney disease (ADPKD) is characterized by mutations in either the PKD1 or PKD2 genes leading to progressive cyst growth and often ESKD. We have previously demonstrated that with loss of Pkd1 the tubules can enlarge without an increase in tubular cell numbers, suggesting that tubular basement membrane remodeling is important for cystic dilation. Here we compared the transcriptomes from inducible tubule-specific knock out of Pkd1 (PkdTKO) and the uninduced littermate mice kidneys as controls. RNA sequencing revealed significant upregulation of 17 metalloproteinases. Of these, A Disintegrin and Metalloproteinase with Thrombospondin Motif 1 (Adamts1), expressed primarily by the proximal tubule, is the most significantly upregulated following loss of Pkd1 expression. Upregulation of Adamts1 in PkdTKO kidneys correlated with a significant increase in the 70 kDa cleavage product of the V1 isoform of versican, which localized to the tubule basement membrane (TBM) and adjacent interstitial mononuclear cells. Simultaneous deletion of both Adamts1 and Pkd1 (P/ATKO) reduced Adamts1 expression levels by >90%, prevented V1 versican cleavage, and reduced interstitial macrophage accumulation and activation. P/ATKO mice demonstrated slower cystic enlargement, improved BUN and creatinine and better survival than did PkdTKO mice. In conclusion, preventing Adamts1 upregulation following loss of tubular Pkd1 expression effectively reduced macrophage accumulation and TBM remodeling, slowing cyst growth and preserving renal function.
2024-09-30 | GSE270531 | GEO
Project description:Polycystic kidney disease (PKD) exhibits an inflammatory component, but the contribution of inflammation to cyst progression is unknown. Macrophages promote the proliferation of tubular cells following ischemic injury, suggesting that they may have a role in cystogenesis. Furthermore, cultured Pkd1-deficient cells express the macrophage chemoattractants Mcp1 and Cxcl16 and stimulate macrophage migration. Here, in orthologous models of both PKD1 and PKD2, abnormally large numbers of alternatively activated macrophages surrounded the cysts. To determine whether pericystic macrophages contribute to the proliferation of cyst-lining cells, we depleted phagocytic cells from Pkd1(fl/fl);Pkhd1-Cre mice by treating with liposomal clodronate from postnatal day 10 until day 24. Compared with vehicle-treated controls, macrophage-depleted mice had a significantly lower cystic index, reduced proliferation of cyst-lining cells, better-preserved renal parenchyma, and improved renal function. In conclusion, these data suggest that macrophages home to cystic areas and contribute to cyst growth. Interruption of these homing and proliferative signals could have therapeutic potential for PKD.
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Project description:Mild reduction in food intake was recently shown to slow polycystic kidney disease (PKD) progression in mouse models, but whether the effect was due to solely reduced calories or some other aspect of the diet has been unclear. We now show that the benefit is due to the induction of ketosis. Time-restricted feeding, without caloric reduction, strongly inhibits mTOR signaling, proliferation, and fibrosis in the affected kidneys in a PKD rat model. A ketogenic diet had a similar effect and led to regression of renal cystic burden. Acute fasting in rat, mouse, and feline models of PKD results in rapid reduction of cyst volume, while oral administration of the ketone β-hydroxybutyrate (BHB) in rats strongly inhibits PKD progression. These results suggest that cystic cells in PKD are metabolically inflexible, which could be exploited by dietary interventions or supplementation with BHB, representing a new therapeutic avenue to treat PKD.
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Project description:The polycystic kidney diseases (PKD) are a group of genetic disorders causing renal failure and death from infancy to adulthood. Arginine vasopressin (AVP) V2 receptor antagonists inhibit cystogenesis in animal models of cystic kidney diseases, presumably by downregulating cAMP signaling, cell proliferation, and chloride-driven fluid secretion. For confirmation that the protective effect of these drugs is due to antagonism of AVP, PCK (Pkhd1(-/-)) and Brattleboro (AVP(-/-)) rats were crossed to generate rats with PKD and varying amounts of AVP. At 10 and 20 weeks of age, PCK AVP(-/-) rats had lower renal cAMP and almost complete inhibition of cystogenesis compared with PCK AVP(+/+) and PCK AVP(+/-) rats. The V2 receptor agonist 1-deamino-8-d-arginine vasopressin increased renal cAMP and recovered the full cystic phenotype of PCK AVP(-/-) rats and aggravated the cystic disease of PCK AVP(+/+) rats but did not induce cystic changes in wild-type rats. These observations indicate that AVP is a powerful modulator of cystogenesis and provide further support for clinical trials of V2 receptor antagonists in PKD.
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Project description:PurposeTo provide a summary of the relevant literature regarding the impact of surgical cyst decortication on hypertension, renal function, and pain management in patients with autosomal dominant polycystic kidney disease (ADPKD).MethodsData collection was conducted via a Medline search using the subject headings autosomal dominant polycystic kidney disease, surgery, decortication, and marsupialization. Additional reports were derived from references included within these articles.ResultsDespite a trend for improved blood pressure control after cyst decortication in some studies, this cumulative review of the literature did not provide consistent evidence supporting the role of this procedure in blood pressure management in patients with ADPKD. Surgical cyst decortication was associated with renal deterioration in a subset of patients with compromised baseline renal function but did not otherwise appear to have a significant impact on renal function in the majority of studies reviewed. Improvement in chronic pain after this procedure was ubiquitously reported across all studies examined.ConclusionsDespite a potential role in blood pressure management in the setting of ADPKD, surgical cyst decortication has not been definitively shown to alleviate hypertension in this clinical setting. Renal function does not appear to improve following this surgery. Patients with compromised baseline renal function appear to be at increased risk for further deterioration in renal function after cyst decortication, although the role of this procedure in altering the natural trajectory of renal failure in this patient subset needs further investigation. Cyst decortication is highly effective in the management of disease-related chronic pain for the majority of patients with ADPKD, providing durable pain relief in this patient population.
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Project description:Polycystic kidney disease (PKD) is a genetic disorder characterized by aberrant renal epithelial cell proliferation and formation and progressive growth of numerous fluid-filled cysts within the kidneys. Previously, we showed that there is elevated Notch signaling compared to normal renal epithelial cells and that Notch signaling contributes to the proliferation of cystic cells. Quinomycin A, a bis-intercalator peptide, has previously been shown to target the Notch signaling pathway and inhibit tumor growth in cancer. Here, we show that Quinomycin A decreased cell proliferation and cyst growth of human ADPKD cyst epithelial cells cultured within a 3D collagen gel. Treatment with Quinomycin A reduced kidney weight to body weight ratio and decreased renal cystic area and fibrosis in Pkd1RC/RC ; Pkd2+/- mice, an orthologous PKD mouse model. This was accompanied by reduced expression of Notch pathway proteins, RBPjk and HeyL and cell proliferation in kidneys of PKD mice. Quinomycin A treatments also normalized cilia length of cyst epithelial cells derived from the collecting ducts. This is the first study to demonstrate that Quinomycin A effectively inhibits PKD progression and suggests that Quinomycin A has potential therapeutic value for PKD patients.
| S-EPMC8251518 | biostudies-literature
Project description:BackgroundPolycystic kidney disease (PKD) involves renal cysts arising from proliferating tubular cells. Autophagy has been recently suggested as a potential therapeutic target in PKD, and mammalian target of rapamycin (mTOR) is a key negative regulator of autophagy. However, the effect of autophagy regulation on cystogenesis has not been elucidated in PKD mice.MethodsClinical validation was performed using GEO datasets and autosomal dominant polycystic kidney disease (ADPKD) patient samples. Newly established PKD and LC3 transgenic mice were used for in vivo verifications, and additional tests were performed in vitro and in vivo using multiple autophagy drugs.FindingsNeither autophagy stimulation nor LC3 overexpression alleviated PKD. Furthermore, we observed the inhibitory effect of an autophagy inhibitor on cysts, indicating its possible therapeutic use in a specific group of patients with ADPKD.InterpretationOur findings provide a novel insight into the pathogenesis related to autophagy in PKD, suggesting that drugs related to autophagy regulation should be considered with caution for treating PKD.Funding sourcesThis work was supported by grants from the Bio & Medical Technology Development Program; the Collaborative Genome Program for Fostering New Post-Genome Industry of the NRF; the Basic Science Program.
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Project description:BackgroundMultiple preclinical studies have highlighted AMP-activated protein kinase (AMPK) as a potential therapeutic target for autosomal dominant polycystic kidney disease (ADPKD). Both metformin and canagliflozin indirectly activate AMPK by inhibiting mitochondrial function, while salsalate is a direct AMPK activator. Metformin, canagliflozin and salsalate (a prodrug dimer of salicylate) are approved for clinical use with excellent safety profile. Although metformin treatment had been shown to attenuate experimental cystic kidney disease, there are concerns that therapeutic AMPK activation in human kidney might require a higher oral metformin dose than can be achieved clinically.MethodsIn this study, we tested metformin-based combination therapies for their additive (metformin plus canagliflozin) and synergistic (metformin plus salsalate) effects and each drug individually in an adult-onset conditional Pkd1 knock-out mouse model (n = 20 male/group) using dosages expected to yield clinically relevant drug levels.FindingsCompared to untreated mutant mice, treatment with salsalate or metformin plus salsalate improved kidney survival (i.e. blood urea nitrogen <20 mmol/L at the time of sacrifice) and reduced cystic kidney disease severity. However, the effects of metformin plus salsalate did not differ from salsalate alone; and neither metformin nor canagliflozin was effective. Protein expression and phosphorylation analyses indicated that salsalate treatment was associated with reduction in mTOR (mammalian target of rapamycin) activity and cellular proliferation in Pkd1 mutant mouse kidneys. Global gene expression analyses suggested that these effects were linked to restoration of mitochondrial function and suppression of inflammation and fibrosis.InterpretationSalsalate is a highly promising candidate for drug repurposing and clinical testing in ADPKD.
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