Journal of The American Society of Nephrology最新文献

Background: Acute kidney injury following ischemia-reperfusion remains a substantial perioperative challenge lacking effective treatment. p21-activated kinase 4 (PAK4), a downstream effector of Rho GTPase, has been explored in hepatic ischemia-reperfusion injury, but its role in renal ischemia-reperfusion is unknown.

Methods: Wild-type and proximal tubule-specific Pak4 knockout mice underwent 25 min of ischemia followed by 24 h of reperfusion injury. Primary tubular cells and HK-2 cells were exposed to hypoxia-reoxygenation injury to investigate the in vitro impact of PAK4. Selective degradation of PAK4 was employed using proteolysis-targeting chimeras (PROTAC) to ameliorate acute kidney injury.

Results: Post-ischemia-reperfusion, the expression of PAK4 was upregulated through hypoxia-inducible factor 1 alpha in mouse kidneys. Deletion of PAK4 in proximal tubule cells, but not in myeloid cells, significantly mitigated ischemia-reperfusion-induced acute kidney injury, as evidenced by decreased levels of blood urea nitrogen, creatinine, tubular necrosis, apoptosis, macrophage infiltration, and lipid accumulation compared to control mice. Further investigation revealed that PAK4 phosphorylated glutathione peroxidase 3 at T47, leading to its proteasomal degradation. Additionally, pretreatment of mice with the PAK4 PROTAC preserved glutathione peroxidase 3 and enhanced fatty acid β-oxidation, thereby protecting against acute kidney injury. In kidney tissues from people with a kidney transplant, elevated levels of PAK4 protein and phosphorylation of glutathione peroxidase 3 at T47 were observed.

Conclusions: Renal tubular PAK4 contributes to tissue damage during ischemia-reperfusion injury, while PAK4 PROTAC mitigates ischemia-reperfusion injury by reducing oxidative stress and promoting fatty acid β-oxidation.

Abstract: Cognitive impairment involves alterations to one's cognitive status that affects their everyday life. Individuals with chronic kidney disease (CKD), and in particular kidney failure, experience higher rates of cognitive impairment compared to the general population. In CKD, 20-70% of individuals have cognitive impairment, but the highest prevalence is described in kidney failure such that dialysis-dependent patients have twice the prevalence of aged-matched controls. In the past 5 years, the number of investigations examining the "kidney-brain axis", mechanisms of CKD-related cognitive impairment, and potential therapeutics have exponentially increased. This review article summarizes recent literature on direct and indirect effects of CKD-associated cognitive impairment with emphasis on uremic toxins; brain injury mechanisms; overlap between CKD-associated cognitive impairment, Alzheimer's disease, and other neurodegenerative diseases; and promising therapeutics. Reviewed therapeutic interventions include: AST-120 [indoxyl sulfate absorbent], CH-223191 [aryl hydrocarbon receptor antagonist], TRAM34 [Kca3.1-specific inhibitor], anakinra [IL-1R inhibitor], marimastat, exercise, supplements, and kidney transplantation. Special focus is placed on translational studies examining uremic toxin-associated pathogenic processes including brain oxidative stress, neuroinflammation, and blood brain barrier dysfunction through in vitro and in vivo models of CKD-associated brain injury. Finally, future research directions are suggested including targeting of cellular senescence abundance with senotherapeutics and capitalizing on anti-inflammatory effects of regenerative, cell-based therapeutics (e.g. mesenchymal stem cells and extracellular vesicles), and use of aged murine models. Collectively, CKD-associated cognitive impairment represents a prevalent condition for which remaining knowledge gaps exist, and scientific advancements are needed to preserve cognitive function and improve the lives of in individuals with CKD.