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

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

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Article numbere0177934
JournalPLoS One
Volume12
Issue number5
DOIs
Publication statusPublished - 01-05-2017

Fingerprint

Autosomal Recessive Polycystic Kidney
octreotide
Octreotide
Rats
animal models
kidneys
Kidney
Polycystic Kidney Diseases
cyclic AMP
Serum
Cyclic AMP
hyperglycemia
disease course
pasireotide
autosomal recessive polycystic kidney disease
glucose
Glucose
Hyperglycemia
Disease Progression
cell communication

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

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title = "Beneficial effect of combined treatment with octreotide and pasireotide in PCK rats, an orthologous model of human autosomal recessive polycystic kidney disease",
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.",
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Beneficial effect of combined treatment with octreotide and pasireotide in PCK rats, an orthologous model of human autosomal recessive polycystic kidney disease. / Kugita, Masanori; Nishii, Kazuhiro; Yamaguchi, Tamio; Suzuki, Atsushi; Yuzawa, Yukio; Horie, Shigeo; Higashihara, Eiji; Nagao, Shizuko.

In: PLoS One, Vol. 12, No. 5, e0177934, 01.05.2017.

Research output: Contribution to journalArticle

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T1 - Beneficial effect of combined treatment with octreotide and pasireotide in PCK rats, an orthologous model of human autosomal recessive polycystic kidney disease

AU - Kugita, Masanori

AU - Nishii, Kazuhiro

AU - Yamaguchi, Tamio

AU - Suzuki, Atsushi

AU - Yuzawa, Yukio

AU - Horie, Shigeo

AU - Higashihara, Eiji

AU - Nagao, Shizuko

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