Pathogenesis Of Septic Acute Kidney Injury Research Articles

Pectolinarigenin alleviated septic acute kidney injury via inhibiting Jak2/Stat3 signaling and mitochondria dysfunction

Sepsis is a systemic inflammatory response to infection, where sepsis-associated acute kidney injury (AKI) is a common morbid disease with a high morbidity and mortality, and however at present no effective therapy exists. Increasing evidence have shown that mitochondrial damage and inflammatory response are important initiating factors in pathogenesis of septic AKI. Natural flavonoid pectolinarigenin exerted anti-inflammatory properties in previous studies, while its role in septic AKI remains unknown. In the study, pectolinarigenin administration significantly ameliorated the dramatic rise of serum creatinine and blood urea nitrogen in lipopolysaccharide (LPS)- and cecal ligation/puncture (CLP)-induced septic mice, respectively. Consistently, LPS/CLP-induced renal damage as implied by histopathological score and the increased injury markers NGAL and KIM-1, which was attenuated by pectolinarigenin. Meanwhile, LPS/CLP triggered proinflammatory cytokine production and inflammation related proteins in the kidneys. However, pectolinarigenin inhibited renal expression of IL-6, IL-1β, TNF-α, and MCP-1 to improve inflammatory response. Furthermore, pectolinarigenin upregulated Bcl-2 protein expression and suppressed apoptotic protein of BAX and cleaved caspase-3 in the kidneys of CLP-induced septic AKI. Mechanistically, LPS could induce the high expression of IL-6 and trigger the phosphorylation of Jak2 and Stat3, while pectolinarigenin remarkably reduced their corresponding levels. Notably, CLP-induced kidney injury of mice significantly reduced the expression of PGC-1α, OPA1 and increased the expression of Drp1, Cyt-C, where pectolinarigenin pretreatment significantly restored their corresponding expression in mice. In summary, pectolinarigenin improved septic AKI via inhibiting JAK2/STAT3 signaling and mitochondria dysfunction.

Septic acute kidney injury: molecular mechanisms and the importance of stratification and targeting therapy.

The most common cause of acute kidney injury (AKI) in hospitalized patients is sepsis. However, the molecular pathways and mechanisms that mediate septic AKI are not well defined. Experiments performed over the past 20 years suggest that there are profound differences in the pathogenesis between septic and ischemic AKI. Septic AKI often occurs independently of hypoperfusion, and is mediated by a concomitant pro- and anti-inflammatory state that is activated in response to various pathogen-associated molecular patterns, such as endotoxin, as well as damage-associated molecular patterns. These molecular patterns are recognized by Toll-like receptors (TLRs) found in the kidney, and effectuate downstream inflammatory pathways. Additionally, apoptosis has been proposed to play a role in the pathogenesis of septic AKI. However, targeted therapies designed to mitigate the above aspects of the inflammatory state, TLR-related pathways, and apoptosis have failed to show significant clinical benefit. This failure is likely due to the protean nature of septic AKI, whereby different patients present at different points along the immunologic spectrum. While one patient may benefit from targeted therapy at one end of the spectrum, another patient at the other end may be harmed by the same therapy. We propose that a next important step in septic AKI research will be to identify where patients lie on the immunologic spectrum in order to appropriately target therapies at the inflammatory cascade, TLRs, and possibly apoptosis.

Histopathological changes in septic acute kidney injury in critically ill children: an observational analytical study of postmortem renal biopsies

Critically ill children often manifest acute kidney injury (AKI) as part of their disease process with incidence up to 82% and it is independently associated with poor outcome [1]. Sepsis is the most common contributing factor and little is known about the pathogenesis of septic AKI. There are no consistent histopathological changes in human or experimental septic AKI [2]. Hence, understanding of the structural changes associated with its occurrence is therefore important in the management of AKI in critically ill children.