High Intrarenal Lactate Production Inhibits the Renal Pseudohypoxic Response to Acutely Induced Hypoxia in Diabetes

Abstract

Intrarenal hypoxia develops within a few days after the onset of insulinopenic diabetes in an experimental animal model (ie, a model of type-1 diabetes). Although diabetes-induced hypoxia results in increased renal lactate formation, mitochondrial function is well maintained, a condition commonly referred to as pseudohypoxia. However, the metabolic effects of significantly elevated lactate levels remain unclear. We therefore investigated in diabetic animals the response to acute intrarenal hypoxia in the presence of high renal lactate formation to delineate mechanistic pathways and compare these findings to healthy control animals. Hyperpolarized 13 C-MRI and blood oxygenation level–dependent 1 H-MRI was used to investigate the renal metabolism of [1- 13 C]pyruvate and oxygenation following acutely altered oxygen content in the breathing gas in a streptozotocin rat model of type-1 diabetes with and without insulin treatment and compared with healthy control rats. The lactate signal in the diabetic kidney was reduced by 12%–16% during hypoxia in diabetic rats irrespective of insulin supplementation. In contrast, healthy controls displayed the well-known Pasteur effect manifested as a 10% increased lactate signal following reduction of oxygen in the inspired air. Reduced expression of the monocarboxyl transporter-4 may account for altered response to hypoxia in diabetes with a high intrarenal pyruvate-to-lactate conversion. Reduced intrarenal lactate formation in response to hypoxia in diabetes shows the existence of a different metabolic phenotype, which is independent of insulin, as insulin supplementation was unable to affect the pyruvate-to-lactate conversion in the diabetic kidney.

Centhaquine Restores Renal Blood Flow and Protects Tissue Damage After Hemorrhagic Shock and Renal Ischemia

“…We observed several fold increase in blood lactate level in rats of all the experimental groups after hemorrhage, which comes down near to baseline at 30 min of post resuscitation, however resuscitation with vehicle didn’t provide sustainable effect and at 120 min post resuscitation the lactate level in NS was observed significantly higher than CQ. Lactate is also known to induce hypoxia inducible factors (HIFs) ( Lee et al, 2015 ; Laustsen et al, 2019 ). HIF1 is a dimeric protein and plays important role in oxygen homeostasis in tissues.…”

Targeting immunometabolism during cardiorenal injury: roles of conventional and alternative macrophage metabolic fuels

“…Given the fact that mitochondrial dysfunction and impaired OXPHOS is a hallmark of DKD, it could be speculated that along with the shift towards glycolysis, lactate oxidation may be impaired, leading to systemic and local increases in lactate (Zhang et al, 2018). As discussed previously, lactate promotes a metabolic shift in fibroblasts to promote a myofibroblast phenotype, leading to renal fibrosis (Ding et al, 2017;Shen et al, 2020) and linking increased lactate in DKD to aggravated injury (Laustsen et al, 2019;Lee et al, 2022). However, the role of macrophage lactate metabolism in T2D remains to be determined.…”