Treatments for Sepsis-Related Acute Kidney Injury May Converge on Mitochondrial Function and Macrophage Polarization
Sepsis is an age-related problem, as the progressive incapacity of the immune system makes it ever more likely that an initiating infection can spiral out of control in this way. Sepsis can attack the kidney on the way to killing the patient. The paper here is focused on one particular fungal dietary supplement used in cases of acute kidney injury, but might be taken more generally as a look at the way in which improved mitochondrial function and adjustment of macrophage polarization towards a pro-regenerative phenotype are the mechanisms by which any protective (rather than pathogen-targeted) therapy should act in the case of sepsis-induced kidney dysfunction.
Sepsis-associated acute kidney injury (S-AKI) is among the most serious and common complications of sepsis. Although S-AKI has attracted widespread attention, the detailed pathophysiological mechanisms of S-AKI remain complicated and poorly understood. Extensive studies have reported various abnormal physiological processes in S-AKI, including impaired energy metabolism, excess oxidative stress, apoptosis and necrosis of renal tubular epithelial cells, impaired renal microcirculation, activation of inflammatory cells, and inflammatory storms. Moreover, because the kidneys are among the most energy-demanding organs in the body, energy metabolism is crucial for proper renal function.
Mitochondrial damage and dysfunction are highly involved in tubular cell injury or death in acute kidney injury. Therefore, maintaining the structural and functional integrity of the mitochondria may prevent tubular cell apoptosis, thereby facilitating renal recovery from acute kidney injury. Furthermore, the macrophage polarization state and production of inflammatory mediators markedly affect the progression of S-AKI. For example, the release of pro-inflammatory cytokines or excessive oxidative stress from M1 macrophages can exacerbate renal injury. Moreover, M2 macrophages releasing anti-inflammatory factors and growth factors have protective effects against kidney damage. Accordingly, renal mitochondria and macrophage polarization may be promising targets for the prevention and mitigation of S-AKI.
Cordyceps sinensis (CS) is a fungus with a long history of use in traditional Chinese medicine, owing to its anti-aging and anti-cancer properties. The active ingredients of CS include cordycepin, polysaccharides, sterols, and phenolic compounds. Because of its broad physiological effects, including antioxidant, anti-fibrotic, and anti-inflammatory activity, CS has been generally used for renal protection. In the present study, we first evaluated the protective and therapeutic effects of CS against LPS-induced AKI in mice via assays including histopathological staining, serum renal function indexes, and inflammatory cytokine analyses. We performed transcriptomic and proteomic assays on kidney tissues, revealing the molecular targets and pathways through which CS ameliorates S-AKI. We confirmed that CS protects the kidneys against S-AKI by synergistically reprogramming mitochondrial energy metabolism and macrophage polarization.