Metabolic Flexibility and Innate Immunity in Renal Ischemia Reperfusion Injury: The Fine Balance Between Adaptive Repair and Tissue Degeneration

Abstract

Renal ischemia reperfusion injury (IRI), a common event after renal transplantation, causes acute kidney injury (AKI), increases the risk of delayed graft function (DGF), primes the donor kidney for rejection, and contributes to the long-term risk of graft loss. In the last decade, epidemiological studies have linked even mild episodes of AKI to chronic kidney disease (CKD) progression, and innate immunity seems to play a crucial role. The ischemic insult triggers an acute inflammatory reaction that is elicited by Pattern Recognition Receptors (PRRs), expressed on both infiltrating immune cells as well as tubular epithelial cells (TECs). Among the PRRs, Toll-like receptors (TLRs), their synergistic receptors, Nod-like receptors (NLRs), and the inflammasomes, play a pivotal role in shaping inflammation and TEC repair, in response to renal IRI. These receptors represent promising targets to modulate the extent of inflammation, but also function as gatekeepers of tissue repair, protecting against AKI-to-CKD progression. Despite the important considerations on timely use of therapeutics, in the context of IRI, treatment options are limited by a lack of understanding of the intra-and intercellular mechanisms associated with the activation of innate immune receptors and their impact on adaptive tubular repair. Accumulating evidence suggests that TEC-associated innate immunity shapes the tubular response to stress through the regulation of immunometabolism. Engagement of innate immune receptors provides TECs with the metabolic flexibility necessary for their plasticity during injury and repair. This could significantly affect pathogenic processes within TECs, such as cell death, mitochondrial damage, senescence, and pro-fibrotic cytokine secretion, well-known to exacerbate inflammation and fibrosis. This article provides an overview of the past 5 years of research on the role of innate immunity in experimental and human IRI, with a focus on the cascade of events activated by hypoxic damage in TECs: from programmed cell death (PCD) and Tammaro et al. Innate Immunity in Renal IRI mitochondrial dysfunction-mediated metabolic rewiring of TECs to maladaptive repair and progression to fibrosis. Finally, we will discuss the important crosstalk between metabolism and innate immunity observed in TECs and their therapeutic potential in both experimental and clinical research.

The dysregulation of metabolic pathways and induction of the pentose phosphate pathway in renal ischaemia–reperfusion injury

“…Lipid accumulation is clearly a common phenotype following renal injury; however, similar to the uncertainties regarding its damaging or beneficial effect, the underlying cause of this phenomenon also requires further study. As ischaemia is known to suppress OXPHOS [13], a major energy‐producing metabolic pathway in the kidney, it is plausible that pathways associated with lipid metabolism could also be affected by an ischaemic event. Our aim was to investigate the alterations in lipid profile and the underlying metabolic pathway rewiring that occurs during IRI.…”

TSC1 Affects the Process of Renal Ischemia-Reperfusion Injury by Controlling Macrophage Polarization

“…Renal ischemia-reperfusion injury is a major risk factor affecting the prognosis of AKI and the functional recovery and long-term survival of grafts after renal transplantation ( 1 ). Innate and adaptive immune cells, such as macrophages, dendritic cells, neutrophils, and lymphocytes, are involved in the pathogenesis of renal injury after ischemia-reperfusion injury (IRI) ( 2 ).…”

Ischemic postconditioning ameliorates acute kidney injury induced by limb ischemia/reperfusion via transforming TLR4 and NF-κB signaling in rats

“…The kidney is highly sensitive to ischemia and hypoxia, and is prone to acute injury in the process of limb I/R injury, which is characterized by blurred swelling in the tubuli epithelium, acute tubular necrosis, inflammatory cellular infiltration, edema, and congestion [ 12 , 13 ]. Acute kidney injury induced by limb I/R involves complex mechanisms, and inflammatory reactions and oxidative stress play an important role in this pathological process [ 11 , 14 , 15 ]. Some characteristic endogenous proteins are produced in the early phase, and previous studies have shown that the Toll-like receptor 4 (TLR4) signaling pathway is closely related to inflammatory response [ 16 ].…”