Beneficial effect of combined treatment with octreotide and pasireotide in PCK rats, an orthologous model of human autosomal recessive polycystic kidney disease.

Masanori Kugita,Yukio Yuzawa,Eiji Higashihara,Atsushi Suzuki,Tamio Yamaguchi,Shizuko Nagao,Kazuhiro Nishii,Shigeo Horie,Giuseppe Remuzzi

doi:10.1371/journal.pone.0177934

Masanori Kugita, Yukio Yuzawa + Show 7 more

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https://doi.org/10.1371/journal.pone.0177934

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Abstract

Increased intracellular cyclic AMP (cAMP) in renal tubular epithelia accelerates the progression of polycystic kidney disease (PKD). Thus, decreasing cAMP levels by an adenylyl cyclase inhibitory G protein activator is considered to be an effective approach in ameliorating PKD. In fact, pasireotide (PAS) was effective in reducing disease progression in animal models of PKD. However, hyperglycemia caused by the administration of PAS is an adverse effect in its clinical use. Whereas, co-administration of octreotide (OCT) with PAS did not increase serum glucose in normal rats. In the current study, we examined the efficacy of combined treatment with OCT and PAS in PCK rats, an autosomal recessive PKD model. Four-week-old PCK males were treated with the long-acting release type of OCT, PAS, or a combination of both (OCT/PAS) for 12 weeks. After termination, serum and renal tissue were used for analyses. Kidney weight, kidney weight per body weight, renal cyst area, renal Ki67 expression, and serum urea nitrogen were significantly decreased either in the PAS or OCT/PAS group, compared with vehicle. Renal tissue cAMP content was significantly decreased by PAS or OCT/PAS treatment, but not OCT, compared with vehicle. As a marker of cellular mTOR signaling activity, renal phospho-S6 kinase expression was significantly decreased by OCT/PAS treatment compared with vehicle, OCT, or PAS. Serum glucose was significantly increased by PAS administration, whereas no difference was shown between vehicle and OCT/PAS, possibly because serum glucagon was decreased either by the treatment of OCT alone or co-application of OCT/PAS. In conclusion, since serum glucose levels are increased by the use of PAS, its combination with OCT may reduce the risk of hyperglycemia associated with PAS monotherapy against PKD progression.

Highlights

Human polycystic kidney disease (PKD) is characterized by the progressive formation of numerous fluid-filled cysts in the kidney, and in most cases, hepatic fibrocystic disorders occur
The cause of the different results between their and our study is not clearly addressed, it may because the study-term of drug treatment, and drug form and dose
Since long-acting release (LAR)-type OCT is being used for the clinical treatment of acromegaly, hypophyseal gigantism, or gastrointestinal hormone-producing tumors, determining its effective dose in rat model and autosomal recessive PKD (ARPKD) patients by a pharmacokinetics study would be an important step

Summary

Introduction

Human polycystic kidney disease (PKD) is characterized by the progressive formation of numerous fluid-filled cysts in the kidney, and in most cases, hepatic fibrocystic disorders occur. Liver cysts are formed from bile ducts connected to the biliary tree embedded in fibrotic tissue, often complicated with ductal plate malformation caused by congenital hepatic fibrosis [4]. In these PKDs, the stimulated cell proliferation of the renal tubule and hepatic bile duct epithelia is caused by increased levels of intracellular adenosine 30,50-cyclic monophosphate (cAMP), a second messenger that upregulates B-Raf/MEK/ERK signaling in animal models and patients [5, 6]. These findings indicate that reducing cAMP production is potentially effective in this disorder

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