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.

Acute Increase of Renal Perfusion Pressure Causes Rapid Activation of mTORC1 (Mechanistic Target Of Rapamycin Complex 1) and Leukocyte Infiltration

“…This was observed in the absence of any rapamycin effects on the acute autoregulation of renal blood flow. Previous studies have found that acute administration of rapamycin had no significant effect on urine volume or sodium excretion as studied in mice, 37 rats, 9,38 and pig. 39 This would suggest that in the presence of rapamycin the elevated RPP may have either enhanced the expression or activity of tubular sodium transporters or suppressed the production of natriuretic substances.…”

Inhibition of mitochondrial autophagy protects donor lungs for lung transplantation against ischaemia‐reperfusion injury in rats via the mTOR pathway

“…18 Wang et al have confirmed that the mTOR pathway plays distinct roles in the process of inflammation and acute lung injury (ALI). 20 Moreover, the mTOR pathway was also reported to exert effects on ALI in mice by mediating mitochondrial autophagy of lung tissue cells. 20 Moreover, the mTOR pathway was also reported to exert effects on ALI in mice by mediating mitochondrial autophagy of lung tissue cells.…”

“…19 The mTOR pathway affects I/R injury in kidneys by regulation of mitochondrial autophagy. 20 Moreover, the mTOR pathway was also reported to exert effects on ALI in mice by mediating mitochondrial autophagy of lung tissue cells. 21 Therefore, the current study was performed aiming to elucidate the mechanism by which mitochondrial autophagy exerts its effect on lung I/R injury by regulating the mTOR pathway.…”

CD47 limits autophagy to promote acute kidney injury

“…The underlying mechanisms regulating autophagy in AKI are not clearly understood and are thought to be negatively regulated in part by mammalian/mechanistic target of rapamycin (mTOR). However, mTOR has competing effects on cell growth, metabolism, and survival, and pharmacological agents that inhibit mTOR (and thus promote autophagy) do not routinely protect the renal parenchyma from IRI (11, 12). Further work is required to identify molecular regulators of autophagy as well as pharmacological agents that selectively, and beneficially, target this pathway.…”