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.