Metabolic reprogramming by the S-nitroso-CoA reductase system protects against kidney injury.


Endothelial nitric oxide synthase (eNOS) is protective against kidney injury, but the molecular mechanisms of this protection are poorly understood. Nitric oxide-based cellular signalling is generally mediated by protein S-nitrosylation, the oxidative modification of Cys residues to form S-nitrosothiols (SNOs). S-nitrosylation regulates proteins in all functional classes, and is controlled by enzymatic machinery that includes S-nitrosylases and denitrosylases, which add and remove SNO from proteins, respectively. In Saccharomyces cerevisiae, the classic metabolic intermediate co-enzyme A (CoA) serves as an endogenous source of SNOs through its conjugation with nitric oxide to form S-nitroso-CoA (SNO-CoA), and S-nitrosylation of proteins by SNO-CoA is governed by its cognate denitrosylase, SNO-CoA reductase (SCoR). Mammals possess a functional homologue of yeast SCoR, an aldo-keto reductase family member (AKR1A1) with an unknown physiological role. Here we report that the SNO-CoA-AKR1A1 system is highly expressed in renal proximal tubules, where it transduces the activity of eNOS in reprogramming intermediary metabolism, thereby protecting kidneys against acute kidney injury. Specifically, deletion of Akr1a1 in mice to reduce SCoR activity increased protein S-nitrosylation, protected against acute kidney injury and improved survival, whereas this protection was lost when Enos (also known as Nos3) was also deleted. Metabolic profiling coupled with unbiased mass spectrometry-based SNO-protein identification revealed that protection by the SNO-CoA-SCoR system is mediated by inhibitory S-nitrosylation of pyruvate kinase M2 (PKM2) through a novel locus of regulation, thereby balancing fuel utilization (through glycolysis) with redox protection (through the pentose phosphate shunt). Targeted deletion of PKM2 from mouse proximal tubules recapitulated precisely the protective and mechanistic effects of S-nitrosylation in Akr1a1 mice, whereas Cys-mutant PKM2, which is refractory to S-nitrosylation, negated SNO-CoA bioactivity. Our results identify a physiological function of the SNO-CoA-SCoR system in mammals, describe new regulation of renal metabolism and of PKM2 in differentiated tissues, and offer a novel perspective on kidney injury with therapeutic implications.

Year of Publication
Date Published
2019 Jan
PubMed ID
PubMed Central ID
Grant list
R01 HL126900 / HL / NHLBI NIH HHS / United States
R01 DK095072 / DK / NIDDK NIH HHS / United States
R35 HL139424 / HL / NHLBI NIH HHS / United States
U10 HL109250 / HL / NHLBI NIH HHS / United States
R01 AG027002 / AG / NIA NIH HHS / United States
P01 HL128192 / HL / NHLBI NIH HHS / United States
T32 GM007250 / GM / NIGMS NIH HHS / United States
R01 DK119506 / DK / NIDDK NIH HHS / United States
P01 HL075443 / HL / NHLBI NIH HHS / United States