Mechanisms and therapeutic targets of ischemic acute kidney injury

Abstract

Acute kidney injury (AKI) due to renal ischemia reperfusion (IR) is a major clinical problem without effective therapy and is a significant and frequent cause of morbidity and mortality during the perioperative period. Although the pathophysiology of ischemic AKI is not completely understood, several important mechanisms of renal IR-induced AKI have been studied. Renal ischemia and subsequent reperfusion injury initiates signaling cascades mediating renal cell necrosis, apoptosis, and inflammation, leading to AKI. Better understanding of the molecular and cellular pathophysiological mechanisms underlying ischemic AKI will provide more targeted approach to prevent and treat renal IR injury. In this review, we summarize important mechanisms of ischemic AKI, including renal cell death pathways and the contribution of endothelial cells, epithelial cells, and leukocytes to the inflammatory response during ischemic AKI. Additionally, we provide some updated potential therapeutic targets for the prevention or treatment of ischemic AKI, including Toll-like receptors, adenosine receptors, and peptidylarginine deiminase 4. Finally, we propose mechanisms of ischemic AKI-induced liver, intestine, and kidney dysfunction and systemic inflammation mainly mediated by Paneth cell degranulation as a potential explanation for the high mortality observed with AKI.

Keywords: Acute kidney injury; Apoptosis; Inflammation; Ischemia reperfusion injury; Mechanism; Necrosis.

Figure 1

Schematic of proposed mechanisms for renal proximal tubular Toll-like receptor 9 (TLR9)-mediated exacerbation of ischemic acute kidney injury (AKI). After renal ischemia reperfusion (IR) injury, endogenous TLR9 is activated by TLR9 ligand (presumably mitochondrial deoxyribonucleic acid [DNA] products), and TLR9 activation leads to NFκB-mediated induction of pro-inflammatory chemokines and cytokines and caspase 3/8-mediated renal tubular apoptosis. IκB, inhibitor of κB; MyD88, myeloid differentiation factor 88; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells.

Figure 2

Schematic of proposed mechanisms for A₁AR-mediated protection against renal ischemia reperfusion (IR) injury. A₁AR activation by adenosine binding to A₁AR induces synthesis of a cytoprotective cytokine interleukin (IL)-11 via extracellular-signal-regulated kinase (ERK) and hypoxia inducible factor 1-alpha (HIF-1α) activation, and IL-11 subsequently induces sphingosine kinase-1 synthesis, which phosphorylates sphingosine to another cytoprotective molecule sphingosine-1-phosphate (S1P). A₁AR also phosphorylates and induces cytoprotective heat shock protein 27 (HSP27) synthesis via p38 MAPK activation, resulting in decreased renal tubular apoptosis and inflammation. A_2AAR and A_2BAR increase cyclic adenosine monophosphate (cAMP) levels by stimulating adenylate cyclase and activating protein kinase A, which causes translocation of cAMP response-element binding protein into nuclear to produce cytoprotection. A₃AR activation seems to stimulate apoptosis and calcium overload, leading to enhanced renal injury after ischemia and reperfusion. AR, adenosine receptor.

Figure 3

Schematic of proposed mechanisms for peptidylarginine deiminase 4 (PAD4)-mediated inflammation via nuclear factor κB essential modulator (NEMO) activation. Released intracellular adenosine triphosphate (ATP) from necrotic renal tubular cells by renal ischemia reperfusion (IR) injury induces PAD4 activation and cytosolic translocation in neighboring renal proximal tubular cells via P₂X7 receptor activation and protein kinase C (PKC) signaling. Activated and translocated PAD4 into the cytoplasm preferentially citrullinates NEMO and induces cytokine/chemokine synthesis and neutrophil infiltration in the kidney via NFκB signaling pathway.IKK, inhibitor of κB (IκB) kinase; IL, interleukin; P₂X₇ receptor, P₂X purinoceptor 7.

Figure 4

Schematic of proposed mechanisms of ischemic acute kidney injury (AKI)-induced liver, intestine, and kidney dysfunction and systemic inflammation. Acute renal ischemic injury causes small intestinal inflammation, intestinal barrier disruption via endothelial and epithelial cell injury, and release of pro-inflammatory cytokines, such as interleukin (IL)-17A and tumor necrosis factor-α (TNF-α), from Paneth cells. Portal delivery of IL-17A by macrophage leads to hepatic injury, including necrosis, apoptosis, and increased generation and systemic release of TNF-α and IL-6, propagating multiorgan injury and systemic inflammation.