3.6 Compound 270 improves the mice acute kidney injury caused by intraperitoneal injection of LPS through attenuating renal inflammation state
The kidney is one of the most vulnerable organs during LPS stimulated sepsis (Zhao et al. , 2020). Histological detection was carried out to assess the degree of injury of renal in LPS injection mice. Analysis of the pathological sections of mice renal in Veh group displayed intact tubular and glomerular structure, a visible nucleus, the cytoplasm was uniformly stained, no degeneration occurred, and no apparent inflammation. In contrast, the LPS-injected mice suffered from severe renal pathological damage, characterized by edema of renal tubular epithelial cells, tubular dilatation, brush border disappearance, tubular cell vacuolization, cytoplasmic degeneration, cells exfoliation, intratubular casts formation and inflammatory cells infiltration. Strikingly, the substantial pathological abnormal was notably mitigated in LPS-induced mice after pretreatment with 270 (Figure 6A).
Creatinine (Crea) and blood urea nitrogen (BUN) are important indicators of the severity of renal dysfunction (Zhaoet al. , 2020). In agreement with the histological renal morphology, compare with Veh group mice, plasma Crea and BUN levels were significantly increased in LPS-treated mice, and administration with 270 obviously restored LPS-triggered changes in a dose-dependent manner (Figure 6B). Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM1) are specific tubular injury biomarkers (Jiang et al. , 2019). As expected, the transcription levels of NGAL and KIM1 were dramatically enhanced in the kidneys after LPS exposure for up to 24 h, and pretreatment with 270 remarkably reversed renal anomalous mRNA expression of NGAL and KIM1 caused by the intraperitoneal administration of LPS (Figure 6C).
In order to examine whether 270 can improve mice kidney tissue inflammation state after LPS injection, we evaluated the expression of inflammatory genes and the activity of NF-κB and JNK signaling pathways. The mRNA levels of TNF-α, IL-1β, IL-6, MCP 1, Nos2 and COX2 in kidney tissue were observably elevated in response to LPS, which were signally prevented by pretreatment with 270 (Figure 6D). Furthermore, LPS markedly upregulated the phosphorylation of IKK, NF-κB and JNK, and increased the degradation of IκB-α in renal tissue, and all these alterations were abrogated by administration with 270 in a dose-dependent manner (Figure 6E,F). Collectively, our investigations concluded that 270 could protect from acute AKI challenged with LPS.