Role of abnormal energy metabolism in the progression of chronic kidney disease and drug intervention

Abstract

Chronic kidney disease (CKD) is a severe clinical syndrome with significant socioeconomic impact worldwide. Orderly energy metabolism is essential for normal kidney function and energy metabolism disorders are increasingly recognized as an important player in CKD. Energy metabolism disorders are characterized by ATP deficits and reactive oxygen species increase. Oxygen and mitochondria are essential for ATP production, hypoxia and mitochondrial dysfunction both affect the energy production process. Renin-angiotensin and adenine signaling pathway also play important regulatory roles in energy metabolism. In addition, disturbance of energy metabolism is a key factor in the development of hereditary nephropathy such as autosomal dominant polycystic kidney disease. Currently, drugs with clinically clear renal function protection, such as Angiotensin II Type 1 receptor blockers and fenofibrate, have been proven to improve energy metabolism disorders. The sodium-glucose co-transporter inhibitors 2 that can mediate glucose metabolism disorders not only delay the progress of diabetic nephropathy, but also have significant protective effects in non-diabetic nephropathy. Hypoxia-inducible factor enhances ATP production to the kidney by improving renal oxygen supply and increasing glycolysis, and the mitochondria targeted peptides (SS-31) plays a protective role by stabilizing the mitochondrial inner membrane. Moreover, several drugs are being studied and are predicted to have potential renal protective properties. We propose that the regulation of energy metabolism represents a promising strategy to delay the progression of CKD.

Keywords: Energy metabolism; chronic kidney disease; drug intervention; hypoxia; mitochondrial dysfunction.

Figure 1.

Mitochondrial electron transport chain.

Figure 2.

Extracellular purinergic catabolic and signaling pathways. Abbreviations: ecto-nucleoside triphosphate diphosphohydrolase (CD39); ecto-5′-nucleotidase (CD73); AMP: adenosine monophosphate; ADP: adenosine diphosphate.

Figure 3.

Regulation of the stability and transcription activity of HIF. Under normoxic conditions, two key proline residues (Pro) of HIF-α are hydroxylated by specific PHD. Following prolyl hydroxylation, HIF-α binds to the pVHL-E3-ubiquitin ligase complex and is rapidly degraded by the proteasome. Meanwhile, FIH hydroxylates the asparaginyl residue (Asn) of HIF-α to prevent the recruitment of CBP/p300 coactivator. During hypoxia, HIF-α becomes stable and moves from the cytoplasm to the nucleus, where it forms a HIF complex with HIF-β and binds to target gene to activate its transcription. Abbreviations: hypoxia-inducible factor (HIF), prolyl hydroxylase domain-containing protein (PHD), von Hippel-Lindau protein (pVHL), factor inhibiting HIF (FIH), CREB-binding protein (CBP), hypoxia response element (HRE).