mTORC1 maintains renal tubular homeostasis and is essential in response to ischemic stress.

Mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cell metabolism and autophagy. Despite widespread clinical use of mTORC1 inhibitors, the role of mTORC1 in renal tubular function and kidney homeostasis remains elusive. By using constitutive and inducible deletion of conditional Raptor alleles in renal tubular epithelial cells, we discovered that mTORC1 deficiency caused a marked concentrating defect, loss of tubular cells, and slowly progressive renal fibrosis. Transcriptional profiling revealed that mTORC1 maintains renal tubular homeostasis by controlling mitochondrial metabolism and biogenesis as well as transcellular transport processes involved in countercurrent multiplication and urine concentration. Although mTORC2 partially compensated for the loss of mTORC1, exposure to ischemia and reperfusion injury exaggerated the tubular damage in mTORC1-deficient mice and caused pronounced apoptosis, diminished proliferation rates, and delayed recovery. These findings identify mTORC1 as an important regulator of tubular energy metabolism and as a crucial component of ischemic stress responses.

Phenylephrine versus cafedrine/theodrenaline (Akrinor) for the treatment of spinal anaesthesia-induced maternal hypotension during caesarean section: a retrospective single-centre cohort study.

OBJECTIVE: The main objective of this study was to assess the impact of phenylephrine and cafedrine/theodrenaline on the mother and newborn after spinal anaesthesia for caesarean section. SETTING: University teaching hospital. DESIGN: A single-centre retrospective data cohort study. PATIENTS: All obstetric patients who were scheduled for caesarean section in a 2-year period. INTERVENTIONS: Administration of either intravenous phenylephrine prophylactically or cafedrine/theodrenaline (Akrinor) reactively to maintain blood pressure after spinal anaesthesia. MAIN OUTCOME MEASURE: Maternal hypotension, heart rate during caesarean section and after admission to IMC, fetal arterial cord pH and base excess levels, maternal volume resuscitation and the use of rescue medication. RESULTS: 852 data sets could be included: n=440 Akrinor, n=412 in the phenylephrine cohort. During caesarean section blood pressure was slightly higher in the phenylephrine group compared with the Akrinor group, while hypotension <100 mm Hg systolic blood pressure (SBP) occurred significantly more often during arrival at the IMC after surgery when phenylephrine was used. Heart rate was lower and rescue medication was significantly more frequently given in the phenylephrine cohort. Irrespective of the medication used, women with baseline levels of <120 mm Hg SBP had a high risk to develop hypotension <100 mm Hg after spinal anaesthesia for caesarean section. While there was no statistical difference in mean umbilical arterial pH levels, the incidence of acidosis, defined as pH <7.2, was significantly higher with phenylephrine. CONCLUSION: Phenylephrine was not superior to Akrinor to treat spinal anaesthesia-induced maternal hypotension during caesarean section. TRIAL REGISTRATION NUMBER: DRKS00025795.

mTORC2 critically regulates renal potassium handling.

The mTOR pathway orchestrates cellular homeostasis. The rapamycin-sensitive mTOR complex (mTORC1) in the kidney has been widely studied; however, mTORC2 function in renal tubules is poorly characterized. Here, we generated mice lacking mTORC2 in the distal tubule (Rictorfl/fl Ksp-Cre mice), which were viable and had no obvious phenotype, except for a 2.5-fold increase in plasma aldosterone. Challenged with a low-Na+ diet, these mice adequately reduced Na+ excretion; however, Rictorfl/fl Ksp-Cre mice rapidly developed hyperkalemia on a high-K+ diet, despite a 10-fold increase in serum aldosterone levels, implying that mTORC2 regulates kaliuresis. Phosphorylation of serum- and glucocorticoid-inducible kinase 1 (SGK1) and PKC-α was absent in Rictorfl/fl Ksp-Cre mice, indicating a functional block in K+ secretion activation via ROMK channels. Indeed, patch-clamp experiments on split-open tubular segments from the transition zone of the late connecting tubule and early cortical collecting duct demonstrated that Ba2+-sensitive apical K+ currents were barely detectable in the majority of Rictorfl/fl Ksp-Cre mice. Conversely, epithelial sodium channel (ENaC) activity was largely preserved, suggesting that the reduced ability to maintain K+ homeostasis is the result of impaired apical K+ conductance and not a reduced electrical driving force for K+ secretion. Thus, these data unravel a vital and nonredundant role of mTORC2 for distal tubular K+ handling.