Renal Cortical Pyruvate Depletion during AKI

Abstract

Pyruvate is a key intermediary in energy metabolism and can exert antioxidant and anti-inflammatory effects. However, the fate of pyruvate during AKI remains unknown. Here, we assessed renal cortical pyruvate and its major determinants (glycolysis, gluconeogenesis, pyruvate dehydrogenase [PDH], and H 2 O 2 levels) in mice subjected to unilateral ischemia (15-60 minutes; 0-18 hours of vascular reflow) or glycerol-induced ARF. The fate of postischemic lactate, which can be converted back to pyruvate by lactate dehydrogenase, was also addressed. Ischemia and glycerol each induced persistent pyruvate depletion. During ischemia, decreasing pyruvate levels correlated with increasing lactate levels. During early reperfusion, pyruvate levels remained depressed, but lactate levels fell below control levels, likely as a result of rapid renal lactate efflux. During late reperfusion and glycerol-induced AKI, pyruvate depletion corresponded with increased gluconeogenesis (pyruvate consumption). This finding was underscored by observations that pyruvate injection increased renal cortical glucose content in AKI but not normal kidneys. AKI decreased PDH levels, potentially limiting pyruvate to acetyl CoA conversion. Notably, pyruvate therapy mitigated the severity of AKI. This renoprotection corresponded with increases in cytoprotective heme oxygenase 1 and IL-10 mRNAs, selective reductions in proinflammatory mRNAs (e.g., MCP-1 and TNF-a), and improved tissue ATP levels. Paradoxically, pyruvate increased cortical H 2 O 2 levels. We conclude that AKI induces a profound and persistent depletion of renal cortical pyruvate, which may induce additional injury.

Renal cortical hexokinase and pentose phosphate pathway activation through the EGFR/Akt signaling pathway in endotoxin-induced acute kidney injury

“…These findings are in agreement with recent reports of renal cortical pyruvate depletion in both I/R and glycerolinduced AKI in mice (75). The same study also reported glycolytic induction in the renal cortex only occurs during the ischemic period and is reversed after reperfusion (75). However, it should be noted that some of the analyses performed here, including pyruvate and lactate measurements, are not sufficiently powered to detect small changes between groups.…”

“…Pyruvate content was decreased approximately twofold at both 3 and 18 h, whereas lactate levels trended toward a decrease at 3 h but returned to baseline levels by 18 h post-LPS. These findings are in agreement with recent reports of renal cortical pyruvate depletion in both I/R and glycerolinduced AKI in mice (75). The same study also reported glycolytic induction in the renal cortex only occurs during the ischemic period and is reversed after reperfusion (75).…”

“…Inhibition of the Na ϩ -K ϩ -ATPase and glycolysis in proximal tubules following complex I inhibition indicated that glycolytic induction serves to promote cellular function and survival (14). In vivo data also reveal that anaerobic glycolysis is increased in the renal cortex during ischemia but rapidly returns to baseline levels after reperfusion (75). These data provide strong evidence that glycolytic metabolism can be activated for energy production in the proximal tubule.…”

“…Glycolytic induction appears to play an important role in maintaining tubular cell viability, producing ATP, and preserving transport processes (14,47,72). In addition, recent studies have demonstrated that glycolytic metabolism is rapidly increased in the cortex in response to renal ischemia in vivo (75). These findings indicate that glycolysis may provide an alternate means of energy generation in response to tubular insult.…”

Novel application of complementary imaging techniques to examine in vivo glucose metabolism in the kidney

“…Historical interpretation of studies from heterogeneous ex vivo preparations suggests that glucose utilization for glycolysis by the proximal tubule is minimal (17, 32). However, recent studies suggest that proximal tubule glycolytic flux plays an important role under various stressors and in diverse pathophysiological conditions (14,15,24,34). Nonetheless, a detailed examination and understanding of kidney glucose metabolism in vivo is lacking in large extent to the absence of tools to examine this process in vivo.…”