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Role of mechanistic target of rapamycin (mTOR) in renal function and ischaemia-reperfusion induced kidney injury.

Abstract：

:Despite the presence of many studies on the role of mechanistic target of rapamycin (mTOR) in cardiorenal tissues, the definitive role of mTOR in the pathogenesis of renal injury subsequent to ischaemia-reperfusion (IR) remains unclear. The aims of the current study were to characterize the role of mTOR in normal kidney function and to investigate the role of mTOR activation in IR-induced kidney injury. In euvolemic anaesthetized rats, treatment with the mTOR inhibitor rapamycin increased blood pressure (121 ± 2 to 144 ± 3 mmHg; P<.05), decreased glomerular filtration rate (GFR; 1.6 ± 0.3 to 0.5 ± 0.2 mL/min; P<.05) and increased urinary sodium excretion (UNaV; 14 ± 1 to 109 ± 25 mmol/L per hour; P<.05). In rats subjected to IR, autophagy induction, p-mTOR expression and serum creatinine increased (1.9 ± 0.2 to 3 ± 0.3 mg/dL; P<.05); treatment with rapamycin blunted p-mTOR expression but further increased autophagy induction and serum creatinine (3 ± 0.3 to 5 ± 0.6 mg/dL; P<.05). In contrast, clenbuterol, an mTOR activator, blunted the effect of rapamycin on serum creatinine (4 ± 0.6 vs 2.3 ± 0.3 mg/dL; P<.05), autophagy induction and p-mTOR expression. IR also increased 24 hour protein excretion (9 ± 3 to 17 ± 2 mg/day; P<.05) and kidney injury molecule-1 (KIM-1) expression, and rapamycin treatment further increased KIM-1 expression. Clenbuterol exacerbated protein excretion (13 ± 2 to 26 ± 4 mg/day; P<.05) and antagonized the effect of rapamycin on KIM-1 expression. Histopathological data demonstrated kidney injury in IR rats that was worsened by rapamycin treatment but attenuated by clenbuterol treatment. Thus, mTOR signalling is crucial for normal kidney function and protecting the kidney against IR injury through autophagy suppression.

journal_name

Clin Exp Pharmacol Physiol

journal_title

Clinical and experimental pharmacology & physiology

authors

Alshaman R,Truong L,Oyekan A

doi

10.1111/1440-1681.12648

subject

Has Abstract

pub_date

2016-11-01 00:00:00

pages

1087-1096

issue

eissn

0305-1870

issn

1440-1681

journal_volume

pub_type

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Role of mechanistic target of rapamycin (mTOR) in renal function and ischaemia-reperfusion induced kidney injury.