Vascular endothelial growth factor as an angiogenesis biomarker for the progression of autosomal dominant polycystic kidney disease

Dp, Martins; Ma, Souza; Me, Baitello; Nogueira,; Ci, Oliveira; Ma, Pinhel; Caldas, Heloisa Cristina; Ma, Filho; Dr, Souza

doi:10.4238/gmr.15017623

Cited by 5 publications

(5 citation statements)

References 20 publications

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“…Extending this concept, we reasoned that identification of signaling intermediates which: (1) regulate multiple steps in a single pathophysiological pathway; in addition to acting as; and (2) an integration point for multiple signaling cascades may provide even greater benefit than EGFR combination therapy noted above. Key integration points for targeting to prevent disease progression include the activation of the EGFR axis, c-Src, and VEGFR2 by specific kinases[ 3 , 34 , 40 , 45 - 50 ] and cAMP signaling[ 51 - 53 ]. This led us to examine the potential of a novel multi-kinase inhibitor, TSV, in preventing progression of ARPKD.…”

Section: Discussionmentioning

confidence: 99%

Tesevatinib ameliorates progression of polycystic kidney disease in rodent models of autosomal recessive polycystic kidney disease

Sweeney¹,

Frost²,

Avner³

2017

WJN

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AIMTo investigate the therapeutic potential of tesevatinib (TSV), a unique multi-kinase inhibitor currently in Phase II clinical trials for autosomal dominant polycystic kidney disease (ADPKD), in well-defined rodent models of autosomal recessive polycystic kidney disease (ARPKD).METHODSWe administered TSV in daily doses of 7.5 and 15 mg/kg per day by I.P. to the well characterized bpk model of polycystic kidney disease starting at postnatal day (PN) 4 through PN21 to assess efficacy and toxicity in neonatal mice during postnatal development and still undergoing renal maturation. We administered TSV by oral gavage in the same doses to the orthologous PCK model (from PN30 to PN90) to assess efficacy and toxicity in animals where developmental processes are complete. The following parameters were assessed: Body weight, total kidney weight; kidney weight to body weight ratios; and morphometric determination of a cystic index and a measure of hepatic disease. Renal function was assessed by: Serum BUN; creatinine; and a 12 h urinary concentrating ability. Validation of reported targets including the level of angiogenesis and inhibition of angiogenesis (active VEGFR2/KDR) was assessed by Western analysis.RESULTSThis study demonstrates that: (1) in vivo pharmacological inhibition of multiple kinase cascades with TSV reduced phosphorylation of key mediators of cystogenesis: EGFR, ErbB2, c-Src and KDR; and (2) this reduction of kinase activity resulted in significant reduction of renal and biliary disease in both bpk and PCK models of ARPKD. The amelioration of disease by TSV was not associated with any apparent toxicity.CONCLUSIONThe data supports the hypothesis that this multi-kinase inhibitor TSV may provide an effective clinical therapy for human ARPKD.

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Section: Discussionmentioning

confidence: 99%

Tesevatinib ameliorates progression of polycystic kidney disease in rodent models of autosomal recessive polycystic kidney disease

Sweeney¹,

Frost²,

Avner³

2017

WJN

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“…Evidence from earlier background studies suggests that angiogenic factors are highly expressed in ADPKD and through the promotion of angiogenesis may contribute toward building of a vascular network that favor cysts progression [12]. Other experimental data indicate that VEGF may also be involved in promoting angiogenic activity in ADPKD [13, 18]. Beyond VEGF, increased expression of other angiogenic factors such as angiopoietin 1 and 2 has been noted in ADPKD models.…”

Section: Discussionmentioning

confidence: 99%

Levels of Endocan, Angiopoietin-2, and Hypoxia-Inducible Factor-1a in Patients with Autosomal Dominant Polycystic Kidney Disease and Different Levels of Renal Function

et al. 2018

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Background: Endothelial dysfunction leading to unbalanced vasoconstriction and ischemia of renal parenchyma is increasingly proposed as an alternative pathway of renal damage in autosomal dominant polycystic kidney disease (ADPKD). However, human studies investigating the evolution of such phenomena are limited. This study investigated the levels of emerging biomarkers of endothelial function, angiogenesis and hypoxia, in ADPKD patients with different renal function. Methods: The study population consisted of three groups: 26 ADPKD patients with impaired renal function (Group A; estimated glomerular filtration rate [eGFR] 45–70 mL/min/1.73 m²), 26 ADPKD patients with preserved renal function (Group B; eGFR >70 mL/min/1.73 m²), and 26 age- and sex-matched controls with no history of renal disease. Circulating levels of endocan (endothelial cell-specific molecule-1) angiopoietin-2, and hypoxia-inducible factor-1a (HIF-1a) were determined by enzyme-linked immunosorbent assay techniques. Results: Patients in Group A had significantly higher levels of endocan (7.17 ± 0.43 ng/mL), angiopoietin-2 (5,595.43 ± 3,390), and HIF-1a (163.68 ± 37.84 pg/mL) compared to patients in Group B (6.86 ± 0.59 ng/mL, p = 0.017, 3,854.41 ± 3,014.30, p = 0.018, 136.84 ± 42.10 pg/mL, p = 0.019 respectively) or controls (4.83 ± 0.69 ng/mL, 1,069 ± 427.88 pg/mL, 70.20 ± 17.49 pg/mL, p < 0.001 for all comparisons). Of note, patients in Group B had also higher levels of all markers compared to controls (p < 0.001) despite having similar renal function. In correlation analyses within ADPKD patients, we noted strong correlations of all studied markers with asymmetric dimethylarginine (ADMA; endocan r = 0.908, p < 0.001, angiopoietin-2 r = 0.983, p < 0.001 and HIF-1a r = 0.998, p < 0.001), and only weak or modest correlations with eGFR. Conclusions: This study suggests that endothelial dysfunction causing microcirculatory changes, linked to angiogenesis and hypoxia, may come early in the course of ADPKD and could be a key regulator of renal injury progression.

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“…For example, Yaghoubian et al ( 87 ) observed that patients with abdominal aortic aneurysms had increased renal cyst incidence rates, indicating that renal cysts may be associated with other types of disease. In addition, previous research on polycystic kidney disease (PKD) identified numerous of the molecular mechanisms that were closely associated with the occurrence of renal cysts, such as genetic mutations in hepatocyte nuclear factor-1β and polycystin-1/2 ( 88 – 90 ), abnormal renin-angiotensin-aldosterone system activation ( 91 ), altered intracellular calcium signalling ( 82 , 92 ), MET oncogene mutations ( 93 ), vasopressin receptor upregulation ( 94 ), mTOR pathway activation ( 95 , 96 ), c-Myc-derived apoptosis ( 97 ), endothelin-1 receptor upregulation ( 98 ), TGF-β1 and apelin pathway activation ( 99 ), VEGF gene variants ( 100 ) and dysfunction of the innate immune system ( 101 ). According to the results of NCBI literature search, there are a few studies evaluating the relationship between telomere and PKD ( 102 – 104 ).…”

Section: Renal Cystsmentioning

confidence: 99%

Roles of telomeres and telomerase in age‑related renal diseases (Review)

Wang

et al. 2020

Mol Med Rep

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age-related renal diseases, which account for various progressive renal disorders associated with cellular and organismal senescence, are becoming a substantial public health burden. However, their aetiologies are complicated and their pathogeneses remain poorly understood. Telomeres and telomerase are known to be essential for maintaining the integrity and stability of eukaryotic genomes and serve crucial roles in numerous related signalling pathways that activate renal functions, such as repair and regeneration. Previous studies have reported that telomere dysfunction served a role in various types of age-related kidney disease through various different molecular pathways. The present review aimed to summarise the current knowledge of the association between telomeres and ageing-related kidney diseases and explored the contribution of dysfunctional telomeres to these diseases. The findings may help to provide novel strategies for treating patients with renal disease. Contents 1. introduction 2. Structural renal changes induced by ageing 3. rcc 4. ageing-associated cKd 5. Kidney fibrosis 6. aKi 7. renal cysts 8. conclusion

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Vascular endothelial growth factor as an angiogenesis biomarker for the progression of autosomal dominant polycystic kidney disease

Cited by 5 publications

References 20 publications

Tesevatinib ameliorates progression of polycystic kidney disease in rodent models of autosomal recessive polycystic kidney disease

Tesevatinib ameliorates progression of polycystic kidney disease in rodent models of autosomal recessive polycystic kidney disease

Levels of Endocan, Angiopoietin-2, and Hypoxia-Inducible Factor-1a in Patients with Autosomal Dominant Polycystic Kidney Disease and Different Levels of Renal Function

Roles of telomeres and telomerase in age‑related renal diseases (Review)

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