Korean J Physiol Pharmacol.  2025 Mar;29(2):165-178. 10.4196/kjpp.24.121.

Oligomeric proanthocyanidin ameliorates sepsis-associated renal tubular injury: involvement of oxidative stress, inflammation, PI3K/AKT and NFκκB signaling pathways

• Cui E
• Wu Q
• Zhu H
• Tian W

• KMID: 2565429
• DOI: http://doi.org/10.4196/kjpp.24.121

Abstract

Sepsis is a potentially fatal infectious disease that easily causes shock and numerous organ failures. The kidney is one of the most susceptible to injury. Early intervention and renal protection significantly minimize patient mortality. Oligomeric proanthocyanidin (OPC), a naturally occurring plant compound, has a high potential for renal protection. This study was aimed at exploring the potential renoprotective role of OPC in sepsis-related renal tubular injury. C57/B6 mice were intraperitoneally injected with lipopolysaccharide (LPS) to simulate sepsis-related acute kidney injury in vivo. Renal function and pathology were assessed. RNA sequencing examined OPC mechanisms against LPS-induced renal injury. Oxidative stress indicators and inflammatory cytokines in blood serum and renal tissues were evaluated. In vitro, MTT assays assess cell viability. Apoptosis cells were detected using Hoechst 33342 and propidium iodide staining. Western blot assessed PI3K/AKT and NFκB signaling pathway proteins. OPC reduced LPS-induced renal tubular injury, improved renal functions and pathological changes, restored glutathione content, superoxide dismutase activity, and catalase activity, inhibited malondialdehyde overproduction, and suppressed LPS-induced overproduction of pro-inflammatory cytokines and the decline of anti-inflammatory cytokines. OPC attenuated LPS-induced cell morphological injury, reduced cell viability loss, and recovered the changes in proteins involved in PI3K/AKT and NFκB signaling pathways in MTEC cells. OPC protects against LPSinduced renal tubular injury by counteracting oxidative stress, inhibiting inflammatory responses, activating the PI3K/AKT signaling pathway, and inhibiting the NFκB signaling pathway. It may provide a viable solution to lessen renal injury in patients with sepsis.

Keyword

Inflammation; NFκB; Oligomeric proanthocyanidin; Oxidative stress; PI3K-AKT; Sepsis-associated renal tubular injury

Figure

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  Fig. 1 Effects of OPC on LPS-induced renal tubular injury in vivo. (A, B) The changes in serum renal function test parameters. OPC (2.5, 5, 10 mg/kg) and ulinastatin (50,000 U/kg) treatments were started 3 days before LPS (10 mg/kg) injection and terminated after the administration of LPS. Blood and renal tissues were collected 24 h after LPS injection (n = 6). (C) Renal histological changes were observed using H&E and PAS staining, showing tubules of the indicated groups. Bar = 200 μm. (D) The renal tubular injury semi-quantitatively scored by histopathologist according to the standards as described above (n = 6). (E) The role of OPC on the expression of N-gal in the kidney. Sample lysates from representative mice renal cortices of the control, LPS, and LPS + OPC 10 mg/kg groups were analyzed using Western blotting (n = 3). (F) Semi-quantitative densitometric analysis of D for N-gal. The p-values are indicated at the top of the bars. OPC, oligomeric proanthocyanidin; LPS, lipopolysaccharide; H&E, hematoxylin and eosin; PAS, Periodic Acid-Schiff; BUN, blood urea nitrogen; Ctrl, control. ####p< 0.0001; ##p < 0.01 versus control. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001 versus LPS, respectively.

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  Fig. 2 Effects of OPC on LPS-induced tubular injury in vitro. (A) The role of OPC on morphological changes of mouse tubular epithelial cells (MTEC) triggered by LPS. MTEC cells were incubated with OPC (5 μM) for 1 h and challenged with LPS (5 μg/ml) and ATP (3 mM) for 1 day. Changes in cell morphology were determined using an inverted microscope (100×). Bar = 400 μm. (B) Effects of OPC on cell viability. Cell viability was tested using the MTT assay (n = 3). (C) Apoptotic staining of MTEC cells. MTEC cells were treated with OPC (5 μM) in a 6-well plate for 1 h and then incubated with LPS (5 μg/ml) + ATP (3 mM) for 1 day. Then, the apoptotic cells were determined using the Hoechst 33342 / PI staining. (D) Percentage of apoptotic cells. The p-values are indicated at the top of the bars. OPC, oligomeric proanthocyanidin; LPS, lipopolysaccharide; PI, propidium iodide; Ctrl, control. ###p < 0.001, ####p < 0.0001 versus control. ***p < 0.001, ****p < 0.0001 versus LPS.

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  Fig. 3 RNA sequencing analysis of differential genes in mice. (A) Scatter plot of differential gene distribution in the kidney among the control and LPS groups. (B) Histogram showing the number of up- and down-regulated differential genes in the kidney among the control and LPS groups. (C) Scatter plot of differential gene distribution in the kidney among the LPS and OPC-treated groups. (D) Histogram showing the number of up- and down-regulated differential genes in the kidney among the LPS- and OPC-treated groups. (E) Heat map showing differential gene distribution in kidney from the control, LPS, and OPC-treated groups. (F) Wenckebach plots showing the number of common differential genes before and after OPC treatment in the LPS model. (G) Bubble plots depicting KEGG signaling network enrichment of differential genes before and after OPC treatment in the LPS model. LPS, lipopolysaccharide; OPC, oligomeric proanthocyanidin; KEGG, Kyoto Encyclopedia of Genes and Genomes; Ctrl, control.

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  Fig. 4 Effects of OPC on LPS-induced oxidative stress injury in the kidney. (A) The content of GSH in renal cortical tissues of the indicated groups (n = 5). (B) The SOD activity in renal cortical tissues of the indicated groups (n = 5). (C) The CTA activity in renal cortical tissues of the indicated groups (n = 5). (D) The content of MDA in renal cortical tissues of the indicated groups (n = 5). The p-values are indicated at the top of the bars. OPC, oligomeric proanthocyanidin; LPS, lipopolysaccharide; GSH, glutathione; SOD, superoxide dismutase; CTA, catalase; MDA, malondialdehyde; ns, not statistically. #p < 0.05, ##p < 0.01 versus control. *p < 0.05, **p < 0.01, and ***p < 0.001 versus LPS, respectively.

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  Fig. 5 Effects of OPC on LPS-induced inflammation in vivo. (A–D) The levels of IL-1β, IL-6, TNF-α, and IL-10 in blood serum from mice. (E–H) The levels of IL-1β, IL-6, TNF-α, and IL-10 in renal tissues from mice. The p-values are indicated at the top of the bars. OPC, oligomeric proanthocyanidin; LPS, lipopolysaccharide; TNF-α, tumor necrosis factor-alpha; IL-1β, interleukin-1 beta; IL-6, interleukin-6; IL-10, interleukin-10, ns, not statistically. #p < 0.05, ##p < 0.01, ###p < 0.001, ####p < 0.0001 versus control. *p < 0.05, **p < 0.01, ***p < 0.001 and ****p < 0.0001 versus LPS, respectively.

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  Fig. 6 Role of OPC in the PI3K/AKT and NF κB signaling pathways against LPS-induced renal tubular injury. (A) Expression of PI3K/AKT signaling pathways in LPS-induced renal tubular injury. Mouse tubular epithelial cells (MTEC) were treated with LPS (5 μg/ml) + ATP (3 mM) in a time-dependent manner. Cell lysates were obtained for Western blotting analysis of p-PI3K, PI3K, p-AKT, and AKT. (B) Analyzing A for a semi-quantitative densitometric ratio of p-PI3K to total-PI3K and p-AKT to total-AKT (n = 3). (C) The influence of OPC on the expression of the PI3K/AKT signaling pathway in MTEC cells, MTEC cells were treated with OPC (5 μM) for 1 h before being exposed to LPS (5 μg/ml) + ATP (3 mM) for 24 h. Cell lysates were obtained for the Western blotting analysis of p-PI3K, PI3K, p-AKT, and AKT. (D) Analyzing C for a semi-quantitative densitometric ratio of p-PI3K to total-PI3K and p-AKT to total-AKT (n = 3). (E) Expression of NFκB signaling pathway induced by LPS In a 6-well plate, MTEC cells were treated with LPS (5 μg/ml) + ATP (3 mM) in a time-dependent manner. Cell lysates were obtained for Western blotting analysis of p-IKKα/β, p-NFκB, NFκB, and GAPDH. (F) Analyzing E for a semi-quantitative densitometric ratio of p-NFκB to total-NFκB and p-IKKα/β to GAPDH (n = 3). (G) The influence of OPC on the expression of NFκB signaling pathway in MTEC cells. MTEC cells were treated with OPC (5 μM) for 1 h before being exposed to LPS (5 μg/ml) + ATP (3 mM) for 24 h. Cell lysates were obtained for the Western blotting analysis of p-IKKα/β, p-NFκB, NFκB, and GAPDH. (H) Analyzing G for a semi-quantitative densitometric ratio of p-NFκB to total-NFκB and p-IKKα/β to GAPDH (n = 3). The p-values are indicated at the top of the bars. OPC, oligomeric proanthocyanidin; LPS, lipopolysaccharide; NFκB, nuclear factor κB; Ctrl, control. #p < 0.05, ##p < 0.01, ###p < 0.001 versus control. *p < 0.05 and **p < 0.01 versus LPS, respectively.

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  Fig. 7 Schematic representation of the mechanisms by which OPC mitigates LPS-induced renal tubular injury. LPS shows significant toxicity in renal tubules, which is attenuated by OPC. LPS inhibits the phosphorylation of PI3K/AKT, which causes the activation of downstream apoptosis-related signaling molecules and accelerates cell death. It also stimulates the NFκB signaling pathway, increases the production of inflammatory cytokines, and aggravates the inflammatory response. OPC reverses these alterations. Additionally, OPC mitigates LPS-induced oxidative stress injury by recovering SOD activity, CTA activity, GSH content, and inhibiting the overproduction of MDA. OPC, oligomeric proanthocyanidin; LPS, lipopolysaccharide; NFκB, nuclear factor κB; GSH, glutathione; SOD, superoxide dismutase; CTA, catalase; MDA, malondialdehyde; TNF-α, tumor necrosis factor-alpha; IL-1β, interleukin-1 beta; IL-6, interleukin-6; IL-10, interleukin-10; ROS, reactive oxygen species.

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