The role of metabolic reprogramming in tubular epithelial cells during the progression of acute kidney injury

Abstract

Acute kidney injury (AKI) is one of the most common clinical syndromes. AKI is associated with significant morbidity and subsequent chronic kidney disease (CKD) development. Thus, it is urgent to develop a strategy to hinder AKI progression. Renal tubules are responsible for the reabsorption and secretion of various solutes and the damage to this part of the nephron is a key mediator of AKI. As we know, many common renal insults primarily target the highly metabolically active proximal tubular cells (PTCs). PTCs are the most energy-demanding cells in the kidney. The ATP that they use is mostly produced in their mitochondria by fatty acid β-oxidation (FAO). But, when PTCs face various biological stresses, FAO will shut down for a time that outlives injury. Recent studies have suggested that surviving PTCs can adapt to FAO disruption by increasing glycolysis when facing metabolic constraints, although PTCs do not perform glycolysis in a normal physiological state. Enhanced glycolysis in a short period compensates for impaired energy production and exerts partial renal-protective effects, but its long-term effect on renal function and AKI progression is not promising. Deranged FAO and enhanced glycolysis may contribute to the AKI to CKD transition through different molecular biological mechanisms. In this review, we concentrate on the recent pathological findings of AKI with regards to the metabolic reprogramming in PTCs, confirming that targeting metabolic reprogramming represents a potentially effective therapeutic strategy for the progression of AKI.

Keywords: Acute kidney injury; Fatty acid oxidation; Glycolysis; Metabolic reprogramming; Proximal tubular epithelial cells.

Fig. 1

Changes in mitochondria result in tubular impairment in AKI. A healthy proximal tubule consists of an intact brush border with tight junctions and contains a network of mitochondria to maintain its function. When a kidney is injured, mitochondria react directly and leads to impaired mitochondrial function and an injured proximal tubule. In the early stages of acute kidney injury (AKI), production of ATP is decreased, accompanied by a reduced level of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC⁃1α) and SIRT3. Harmonious interaction between fusion and fission of mitochondria plays an essential role and maintains mitochondrial homeostasis. Fusion of mitochondria is mediated by mitofusin 1 and 2 (MFN1 and MFN2), the outer mitochondrial membrane fusion protein and optic atrophy 1 (OPA1), the inner mitochondrial membrane fusion protein together. Besides, dynamin-related protein 1 (DRP1), a mitochondrial fission protein translocates into the mitochondria and binds with mitochondrial fission 1 (FIS1) to induce mitochondrial fragmentation. Taken together, these events trigger activation and accumulation of DRP1 and FIS1, thus promoting mitochondrial fragmentation and inducing cell death eventually. Cell death induced by mitochondrial dysfunction in injured proximal tubules triggers nuclei loss and tight junctions, and disrupts cellular brush borders

Fig. 2

Energetic metabolic reprogramming of proximal tubular epithelial cells during AKI. Kidneys prefer fatty acids (FAs) for energy production. CD36 facilitates the uptake of FAs in proximal tubular epithelial cells. FAs mainly stored in global triglyceride pool to produce ATP. In cytosol, FAs are activated to acyl-CoA and transported to mitochondria by the carnitine shuttle. In the outer mitochondrial membrane, carnitine palmitoyl-transferase 1 (CPT-1) catalyzes transesterification from acyl-CoA to acylcarnitine. However, CPT1 decreased significantly during AKI and reduced ATP production. Intracellular FAs accumulation positively regulates expression of enzymes in FAO transcriptionally via activating peroxisome proliferator activated receptor-alpha (PPARα). But in AKI, level of PPAR-α, and its DNA binding activity decreases which inhibits transcription of FAO related enzymes. In the meanwhile, hexokinase (HK) is activated to increase glucose-6-phosphate dehydrogenase activity when AKI is induced. Besides, activated hypoxia-induced factor-1 (HIF-1α) induces expression of M2 isoform of pyruvate kinase (PKM2) and slows down the conversion of phosphoenol pyruvate to pyruvate. Moreover, HIF-1α promotes the transformation of pyruvate into lactate and inhibits the transformation from pyruvate into acetyl-CoA, thus blocking its entry into the Krebs cycle