mTOR inhibitor everolimus ameliorates progressive tubular dysfunction in chronic renal failure rats

Shunsaku Nakagawa, Satohiro Masuda, Kumiko Nishihara, Ken ichi Inui

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Responsible factors in progressive tubular dysfunction in chronic renal failure have not been fully identified. In the present study, we hypothesized that the mammalian target of rapamycin, mTOR, was a key molecule in the degenerative and progressive tubular damage in chronic renal failure. Everolimus, an mTOR inhibitor, was administered for 14 days in 5/6 nephrectomized (Nx) rats at 2 and 8 weeks after renal ablation. Marked activation of the mTOR pathway was found at glomeruli and proximal tubules in remnant kidneys of Nx rats. The reduced expression levels of the phosphorylated S6 indicated the satisfactory pharmacological effects of treatment with everolimus for 14 days. Everolimus suppressed the accumulation of smooth muscle alpha actin, infiltration of macrophages and expression of kidney injury molecule-1 in the proximal tubules. In addition, everolimus-treatment restored the tubular reabsorption of albumin, and had a restorative effect on the expression levels of membrane transporters in the polarized proximal tubular epithelium, when its administration was started at 8 weeks after Nx. These results indicate that the constitutively activated mTOR pathway in proximal tubules has an important role in the progressive tubular dysfunction, and that mTOR inhibitors have renoprotective effects to improve the proximal tubular functions in end-stage renal disease.

Original languageEnglish
Pages (from-to)67-76
Number of pages10
JournalBiochemical Pharmacology
Volume79
Issue number1
DOIs
Publication statusPublished - Jan 1 2010

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Chronic Kidney Failure
Rats
Kidney
S 6
Molecules
Membrane Transport Proteins
Macrophages
Sirolimus
Ablation
Infiltration
Smooth Muscle
Muscle
Actins
Albumins
Epithelium
Chemical activation
Pharmacology
Everolimus
Wounds and Injuries

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

Cite this

mTOR inhibitor everolimus ameliorates progressive tubular dysfunction in chronic renal failure rats. / Nakagawa, Shunsaku; Masuda, Satohiro; Nishihara, Kumiko; Inui, Ken ichi.

In: Biochemical Pharmacology, Vol. 79, No. 1, 01.01.2010, p. 67-76.

Research output: Contribution to journalArticle

Nakagawa, Shunsaku ; Masuda, Satohiro ; Nishihara, Kumiko ; Inui, Ken ichi. / mTOR inhibitor everolimus ameliorates progressive tubular dysfunction in chronic renal failure rats. In: Biochemical Pharmacology. 2010 ; Vol. 79, No. 1. pp. 67-76.
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