Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease

Leuenroth, Stephanie J.; Okuhara, Dayne; Shotwell, Joseph D.; Markowitz, Glen S.; Yu, Zhiheng; Somlo, Stefan; Crews, Craig M.

doi:10.1073/pnas.0700499104

Cited by 213 publications

(165 citation statements)

References 49 publications

(58 reference statements)

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“…Although caution should be exercised when interpreting results of experiments using chemical inhibitors, it is nevertheless interesting and perhaps instructive that the PKD state can be phenocopied by these treatments (4), that PKD can be exacerbated by calcium restriction (33), and that raising intracellular calcium can normalize ADPKD cells (34). Certainly, when thinking about potential therapies for ADPKD, one should consider methods that raise basal intracellular calcium levels (41).…”

Section: Camp-dependent Cell Proliferationmentioning

confidence: 99%

Strategies to Inhibit Cyst Formation in ADPKD

Calvet

2008

Clinical Journal of the American Society of Nephrology

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The many hundreds of cysts that grow and expand and ultimately overwhelm and destroy polycystic kidneys arise from the slow but unrelenting proliferation of tubular epithelial cells, eventually giving rise to very large, thin-walled, fluid-filled structures. The growth of these cystic bodies requires two processes: Cell proliferation and fluid secretion. Cyst epithelial cells seem to have a unique phenotype that could offer opportunities for therapeutic intervention. Current evidence has demonstrated that cAMP drives both abnormal cell proliferation, by stimulating the Ras/mitogen-activated protein kinase (MAPK) pathway, and cyst-filling fluid secretion, by activating the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Both of these cAMP-mediated processes should be considered in the design of strategies targeted to slow cyst growth and enlargement in autosomal dominant polycystic kidney disease.Clin Cyst FormationEach cyst that develops in autosomal dominant polycystic kidney disease (ADPKD) is thought to initiate from somatic mutation, causing biallelic loss of PKD gene function (1), or from haploinsufficiency or a threshold effect (2). In ADPKD, a deficiency of the proteins polycystin-1 and polycystin-2, the products of the PKD1 and PKD2 genes, causes cyst formation. Loss of the polycystins is thought to disrupt normal intracellular calcium signaling (3-10); one question begging an answer is what this calcium is normally doing. Once the cyst-initiating event has occurred, it is envisioned that the tubule undergoes a dilation process that involves abnormal cell growth and proliferation. As the cyst grows in size and pinches off from the remainder of the tubule, it then becomes an isolated, selfcontained structure. The cyst continues to enlarge through a proliferative process increasing in cell number and size, and it fills as it enlarges by the secretion of fluid into the cyst lumen (11). Cyst growth occurs slowly, over decades, and eventually the cystic kidneys fail in approximately half of affected individuals by the time they reach their 50s. If cyst growth and enlargement could be slowed, then renal failure could be put off by years or decades, thereby effectively delaying or preventing ESRD.Given this cyst-forming scenario, PKD in theory could be treated by preventing the earliest initiating event either by preventing the somatic second-hit mutations or by upregulating the expression of the unmutated PKD allele; however, with our present state of knowledge, we have no effective way of preventing somatic mutations or controlling PKD protein levels in vivo. Short of that, is it possible to inhibit cyst formation early in the disease when small tubule dilations are first developing? And can we stop cyst growth once it has started? cAMP-Dependent Fluid SecretionIn trying to answer the first of the two questions posed, we used a mutant Pkd1 mouse model, which, as homozygous Pkd1-deficient mice, develop polycystic kidneys as embryos (12). To examine the process of cyst formation at...

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Section: Camp-dependent Cell Proliferationmentioning

confidence: 99%

Strategies to Inhibit Cyst Formation in ADPKD

Calvet

2008

Clinical Journal of the American Society of Nephrology

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“…İn vitro embriyonik fare çalışmalarında gösterilmiştir ki, triptolid, polisistin-2'ye bağlanarak kalsiyum salınımına, bu durum da hücre proliferasyonunu önleyerek kist yükünde azalmaya neden olur. 49 ODPBH oluştu-rulmuş yenidoğan farelerde triptolid, kist büyüme-sini erken evrede inhibe ederek postnatal 8. günde renal fonksiyonu belirgin derecede düzeltmiştir. 50 Hayvan modellerinde, "mammalian target of rapamycin (mTOR)" inhibitörü olan sirolimusun kist büyümesini suprese ettiği ve total böbrek volü-münde azalmaya neden olduğu gösterilmiştir.…”

Section: Otozomal Domi̇nant Poli̇ki̇sti̇k Böbrek Hastaliğiunclassified

A General Overview to the Treatment of Cystic Renal Diseases and Innovations in the Treatment: Review

Zeybek¹,

Orman²,

Gök³

2015

Turkiye Klinikleri J Pediatr

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“…132 In animal models of ADPKD, triptolide restores calcium signaling, attenuates cyst formation, and improves renal function. [133][134][135] In a small uncontrolled clinical study of …”

Section: Triptolidementioning

confidence: 99%

Autosomal dominant polycystic kidney disease: genetics, epidemiology, and treatment

Reed-Gitomer¹

2014

AGG

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Abstract:Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially lethal genetic disorder, accounting for 2%-8% of end-stage renal disease worldwide. While development of renal cysts is the major characteristic of ADPKD, several disease-related complications contribute significantly to morbidity and mortality. Since introduction of renal replacement therapies, cardiovascular disease is the leading cause of death among ADPKD patients. Loss of renal function requiring renal replacement therapy occurs in 50% of patients by the age of 60 years. The results of recent large epidemiological studies in ADPKD have shown little progress in delaying onset of renal failure despite an improvement in patient mortality. Significant progress has been made over the past decade in elucidating the genetics of the disorder. Genetic testing is now available in most countries, and development of more reliable methods for prenatal diagnosis of ADPKD has increased the sensitivity of testing. While there are no approved drugs for treatment of ADPKD within the USA, the first agent targeting renal disease progression in this disorder was recently approved for clinical use in Japan. Furthermore, several additional drugs for treatment of ADPKD are currently under clinical investigation. Overall, this presents an optimistic future for new therapeutic interventions in this disease. This paper reviews the current knowledge related to the epidemiology, genetics, and treatment of ADPKD.

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Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease

Cited by 213 publications

References 49 publications

Strategies to Inhibit Cyst Formation in ADPKD

Strategies to Inhibit Cyst Formation in ADPKD

A General Overview to the Treatment of Cystic Renal Diseases and Innovations in the Treatment: Review

Autosomal dominant polycystic kidney disease: genetics, epidemiology, and treatment

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