Mammalian target of rapamycin regulate kidney oxygen consumption by controlling mitochondrial function via regulation of uncoupling protein 2

Abstract

Excessive kidney oxygen consumption (QO2) without concomitantly increased delivery results in tissue hypoxia, which is a common pathway to the development of kidney disease, including diabetic nephropathy. Mammalian target of rapamycin (mTOR) regulates cell proliferation but also mitochondrial function. However, the role for kidney QO2 is presently unknown. We therefore investigated in vivo QO2 and also studied specific mechanisms using isolated mitochondria from control and diabetic rats.Control and streptozotocin‐diabetic rats were administered rapamycin (0.15 mg/day) for 14 days. Kidney function was measured under Inactin anesthesia.Inhibition of mTOR increased kidney QO2 (+121% and +31%) and decreased tubular transport efficiency (−50% and −36%) in both controls and diabetics without affecting glomerular filtration rate. mTOR inhibition increased QO2 of isolated mitochondria by inducing uncoupling via uncoupling protein‐2.In conclusion, mTOR inhibition increases kidney QO2 by inducing mitochondrial uncoupling, which may aggravate tissue hypoxia. Thus, mTOR inhibition in patients with pre‐existing nephropathy may accelerate the progression of disease.