mTOR inhibitor everolimus ameliorates progressive tubular dysfunction in chronic renal failure rats.
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.
Nakagawa
Shunsaku
S
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
Masuda
Satohiro
S
Nishihara
Kumiko
K
Inui
Ken-Ichi
K
D000818:Animals; D018450:Disease Progression; D000068338:Everolimus; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects* / Q000473:pathology; D008297:Male; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases
D047428:Protein Kinase Inhibitors; D000068338:Everolimus; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus