Effect and mechanism of short-chain fatty acids on inflammation and fibrosis of mice with renal ischemia-reperfusion injury

doi:10.3877/cma.j.issn.2095-3216.2024.04.001

Abstract

Abstract:

Objective

To explore the effect and mechanism of short-chain fatty acid (SCFAs) on inflammation and fibrosis of mice with renal ischemia-reperfusion (I/R) injury.

Methods

The mouse model of renal fibrosis was established by I/R injury induced by bilateral renal artery clamping for 25 minutes. The successfully modeled mice were randomly divided into I/R group, short-chain fatty acid (I/R+ SCFAs) group, SCFAs plus anti-CD25 monal clonal antibody (I/R+ SCFAs+ anti-CD25) group with 6 mice in each group. Besides, there was also a sham operation group in which renal arteries of the mice were isolated without clamping. Mice of the I/R+ SCFAs group and the I/R+ SCFAs+ anti-CD25 group began to drink SCFAs solution continuously one week before the operation, and I/R+ SCFAs+ anti-CD25 group also received intraperitoneal injection of anti-CD25 two days before operation and on the day after the operation. After 28 days of the modeling, kidney tissues of the mice in each group were collected for pathological detection. The expression of CD68, tumor necrosis factor α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), forkhead box transcription factor P3 (Foxp3), and transcription factor retinoic-related orphan receptor γt (RORγt) were detected by immunohistochemistry. Western blotting was applied to detect the expression levels of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear transcription factor κB p65 (NF-κB p65) and α-SMA in renal tissues of all groups.

Results

Compared with sham operation group, the I/R group showed more serious renal pathological injury with renal tubule interstitial fibrosis being increased, and the expressions of CD68, TNF-α, and ICAM-1 in renal tissues were significantly increased in immunohistochemical detection (all P<0.05), while the expression levels of TLR4, MyD88, NF-κB p65, and α-SMA were significantly increased in Western blotting (all P<0.05). Compared with the I/R group, the I/R+ SCFAs group displayed lower level of renal fibrosis, and lower expressions of CD68, TNF-α, and ICAM-1 in renal tissues, while the protein expression levels of TLR4, MyD88, NF-κB p65, and α-SMA were also decreased (all P<0.05). Compared with the I/R+ SCFAs, the I/R+ SCFAs+ anti-CD25 group showed more serious pathological damage, with the Foxp3 expression being decreased, while the expressions of TNF-α, ICAM-1, and RORγt were increased (all P<0.05), and the expression levels of TLR4, MyD88, NF-κB p65, and α-SMA did not show a significant increase.

Conclusion

SCFAs may inhibit the production of inflammatory factors through the TLR4/MyD88/NF-κB pathway, thereby alleviating renal inflammation and renal fibrosis.

Key words: Inflammation, Renal fibrosis, Short-chain fatty acids, Toll-like receptor 4, Regulatory T cells

Jingting Sun, Na Li, Minghui Luo, Yaoyao Gao, Yihang Bai, Guozhen Zhu. Effect and mechanism of short-chain fatty acids on inflammation and fibrosis of mice with renal ischemia-reperfusion injury[J]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2024, 13(04): 181-187.

/ / Recommend

Add to citation manager EndNote|Ris|BibTeX

URL: https://zhsbyjdzzz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.2095-3216.2024.04.001

https://zhsbyjdzzz.cma-cmc.com.cn/EN/Y2024/V13/I04/181

Figures/Tables 4

References 25

[1]	Pickkers P, Darmon M, Hoste E, et al. Acute kidney injury in the critically ill: an updated review on pathophysiology and management [J]. Intensive Care Med, 2021, 47(8): 835-850.
[2]	Selby NM, Taal MW. Long-term outcomes after AKI—a major unmet clinical need [J]. Kidney Int, 2019, 95(1): 21-23.
[3]	Wang Z, Zhang C. From AKI to CKD: maladaptive repair and the underlying mechanisms [J]. Int J Mol Sci, 2022, 23(18): 10880.
[4]	Qi M, Zheng L, Qi Y, et al. Dioscin attenuates renal ischemia/reperfusion injury by inhibiting the TLR4/MyD88 signaling pathway via up-regulation of HSP70 [J]. Pharmacol Res, 2015, 100: 341-352.
[5]	Chen M, Wen X, Gao Y, et al. IRF-4 deficiency reduces inflammation and kidney fibrosis after folic acid-induced acute kidney injury [J]. Int Immunopharmacol, 2021, 100: 108142.
[6]	Jang HR, Rabb H. Immune cells in experimental acute kidney injury [J]. Nat Rev Nephrol, 2015, 11(2): 88-101.
[7]	Xu J, Li X, Yuan Q, et al. The semaphorin 4A-neuropilin 1 axis alleviates kidney ischemia reperfusion injury by promoting the stability and function of regulatory T cells [J]. Kidney Int, 2021, 100(6): 1268-1281.
[8]	Mehrotra P, Ullah MM, Collett JA, et al. Mutation of RORγt reveals a role for Th17 cells in both injury and recovery from renal ischemia-reperfusion injury [J]. Am J Physiol Renal Physiol, 2020, 319(5): F796-F808.
[9]	Snelson M, de Pasquale C, Ekinci EI, et al. Gut microbiome, prebiotics, intestinal permeability and diabetes complications [J]. Best Pract Res Clin Endocrinol Metab, 2021, 35(3): 101507.
[10]	Li LZ, Tao SB, Ma L, et al. Roles of short-chain fatty acids in kidney diseases [J]. Chin Med J (Engl), 2019, 132(10): 1228-1232.
[11]	钟晨瑜，蔡珂丹. 短链脂肪酸在慢性肾脏病中作用及机制的研究进展[J]. 中国病理生理杂志，2021, 37(10): 1900-1904.
[12]	Takagaki Y, Lee SM, Dongqing Z, et al. Endothelial autophagy deficiency induces IL6-dependent endothelial mesenchymal transition and organ fibrosis [J]. Autophagy, 2020, 16(10): 1905-1914.
[13]	Chen J, Li D. Telbivudine attenuates UUO-induced renal fibrosis via TGF-β/Smad and NF-κB signaling [J]. Int Immunopharmacol, 2018, 55: 1-8.
[14]	Humphreys BD. Mechanisms of renal fibrosis [J]. Annu Rev Physiol, 2018, 80: 309-326.
[15]	Liu Y, Lei H, Zhang W, et al. Pyroptosis in renal inflammation and fibrosis: current knowledge and clinical significance [J]. Cell Death Dis, 2023, 14(7): 472.
[16]	Vidya MK, Kumar VG, Sejian V, et al. Toll-like receptors: significance, ligands, signaling pathways, and functions in mammals [J]. Int Rev Immunol, 2018, 37(1): 20-36.
[17]	Li R, Guo Y, Zhang Y, et al. Salidroside ameliorates renal interstitial fibrosis by inhibiting the TLR4/NF-κB and MAPK signaling pathways [J]. Int J Mol Sci, 2019, 20(5): 1103-1119.
[18]	Raphael I, Joern RR, Forsthuber TG. Memory CD4^＋ T cells in immunity and autoimmune diseases [J]. Cells, 2020, 9(3): 531.
[19]	Mehrotra P, Ullah MM, Collett JA, et al. Mutation of RORγt reveals a role for Th17 cells in both injury and recovery from renal ischemia-reperfusion injury [J]. Am J Physiol Renal Physiol, 2020, 319(5): F796-F808.
[20]	Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4^＋CD25^＋ regulatory T cells [J]. Nat Immunol, 2003, 4(4): 330-336.
[21]	Dellepiane S, Leventhal JS, Cravedi P. T cells and acute kidney injury: a two-way relationship [J]. Front Immunol, 2020, 11: 1546.
[22]	Bavikar P, Dighe T, Wakhare P, et al. Role of T-lymphocytes in kidney disease [J]. Cureus, 2021, 13(10): e19153.
[23]	Furusawa Y, Obata Y, Fukuda S, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells [J]. Nature, 2013, 504(7480): 446-450.
[24]	Smith PM, Howitt MR, Panikov N, et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis [J]. Science, 2013, 341(6145): 569-573.
[25]	Johnson MC, Garland AL, Nicolson SC, et al. β-cell-specific IL-2 therapy increases islet Foxp3＋Treg and suppresses type 1 diabetes in NOD mice [J]. Diabetes, 2013, 62(11): 3775-3784.

Please choose a citation manager

Content to export