Septic acute kidney injury (AKI) is the most common type of acute kidney failure observed in hospitalized patients, with inflammation playing a central role in its pathogenesis. The study aimed to investigate the influence of Rehmannioside A (Re A), a natural ingredient from the traditional Chinese herb Rehmanniae radix, on renal dysfunction and inflammation in septic AKI. Peripheral venous blood specimens were obtained from septic patients with and without AKI for comparing their clinical profiles. A rat model of sepsis was established through cecal ligation and puncture (CLP) surgery, followed by intraperitoneal injections of Re A. Biochemical analysis was performed to measure concentrations of kidney function indicators including blood urea nitrogen (BUN) and serum creatinine (Scr). Structural changes in kidney samples were evaluated by hematoxylin-eosin staining. Colony forming units of bacteria were counted in blood and renal samples of rats. Enzyme-linked immunosorbent assay was performed to measure serum and renal levels of proinflammatory cytokines (TNF? and IL-1?). Protein levels of factors related to MAPK and NF-?B pathways were quantified by western blotting. AKI patients showed increases in sepsis-related organ failure assessment (SOFA) score, BUN, Scr, TNF? and IL-1? levels compared to non-AKI patients. Re A improved the survival rate of CLP model rats and reversed CLP-induced increase in BUN and Scr levels. Pathological changes including renal tubular swelling and luminal narrowing induced by CLP were effectively ameliorated by Re A. In addition, Re A reduced bacterial load and proinflammatory cytokine levels in both blood and renal samples. As to the mechanism, Re A inactivated the phosphorylated levels of p38 MAPK and p65 NF-?B rat kidney samples. Re A plays renal-protective and anti-inflammatory properties in the rat model of septic AKI by inhibiting the activation of p38 MAPK and p65 NF-?B signaling. Keywords Acute kidney injury " Inflammation " Rehmannioside A " Renal dysfunction " Sepsis.

Department of Critical Care Medicine The Affiliated Jiangning Hospital of Nanjing Medical University Nanjing China

Zobrazit více v PubMed

Zhang H, Wang Y, Qu M, Li W, Wu D, Cata JP, Miao C. Neutrophil, neutrophil extracellular traps and endothelial cell dysfunction in sepsis. Clin Transl Med. 2023;13:e1170. doi: 10.1002/ctm2.1170. PubMed DOI PMC

Arora J, Mendelson AA, Fox-Robichaud A. Sepsis: network pathophysiology and implications for early diagnosis. Am J Physiol Regul Integr Comp Physiol. 2023;324:R613–r624. doi: 10.1152/ajpregu.00003.2023. PubMed DOI PMC

Chen L, Wu X, Qin H, Zhu H. The PCT to Albumin Ratio Predicts Mortality in Patients With Acute Kidney Injury Caused by Abdominal Infection-Evoked Sepsis. Front Nutr. 2021;8:584461. doi: 10.3389/fnut.2021.584461. PubMed DOI PMC

Boldingh QJ, de Vries FE, Boermeester MA. Abdominal sepsis. Curr Opin Crit Care. 2017;23:159–166. doi: 10.1097/MCC.0000000000000388. PubMed DOI

Luo CJ, Luo F, Bu QD, Jiang W, Zhang W, Liu XM, Che L, Luan H, Zhang H, Ma RX, Sun JP, Xu Y. Protective effects of resveratrol on acute kidney injury in rats with sepsis. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2020;164:49–56. doi: 10.5507/bp.2019.006. PubMed DOI

Poston JT, Koyner JL. Sepsis associated acute kidney injury. Bmj. 2019;364:k4891. doi: 10.1136/bmj.k4891. PubMed DOI PMC

Zhang B, Xue Y, Zhao J, Jiang H, Zhu J, Yin H, Qiu Y, Hu A, Xu L, Song Y, Wang X. Shionone attenuates sepsis-induced acute kidney injury by regulating macrophage polarization via the ECM1/STAT5 Pathway. Front Med (Lausanne) 2021;8:796743. doi: 10.3389/fmed.2021.796743. PubMed DOI PMC

Kolbe KR, Sanches TR, Fanelli C, Garnica MR, Urbano de Castro L, Gooch K, Thomas S, Taylor S, Gorringe A, Noronha IL, Andrade L. Acute kidney injury in a mouse model of meningococcal disease. Int J Immunopathol Pharmacol. 2021;35:20587384211056507. doi: 10.1177/20587384211056507. PubMed DOI PMC

Liu D, Zhong Z, Karin M. NF-κB: A Double-Edged Sword Controlling Inflammation. Biomedicines. 2022:10. doi: 10.3390/biomedicines10061250. PubMed DOI PMC

Zhang Y, Liu F, Jia Q, Zheng L, Tang Q, Sai L, Zhang W, Du Z, Peng C, Bo C, Zhang F. Baicalin alleviates silica-induced lung inflammation and fibrosis by inhibiting TLR4/NF-?B pathway in rats. Physiol Res. 2023;72:221–233. doi: 10.33549/physiolres.934978. PubMed DOI PMC

Yu H, Lin L, Zhang Z, Zhang H, Hu H. Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study. Signal Transduct Target Ther. 2020;5:209. doi: 10.1038/s41392-020-00312-6. PubMed DOI PMC

Behl T, Rana T, Alotaibi GH, Shamsuzzaman M, Naqvi M, Sehgal A, Singh S, Sharma N, Almoshari Y, Abdellatif AAH, Iqbal MS, Bhatia S, Al-Harrasi A, Bungau S. Polyphenols inhibiting MAPK signalling pathway mediated oxidative stress and inflammation in depression. Biomed Pharmacother. 2022;146:112545. doi: 10.1016/j.biopha.2021.112545. PubMed DOI

Lv W, Cao D, Yang F. Trigonelline attenuated sepsis-induced acute kidney injury by activating NAD+/SIRT1 Pathway. Physiol Res. 2025;74:439–447. doi: 10.33549/physiolres.935486. PubMed DOI PMC

Zhu XX, Zheng GL, Lu QB, Su JB, Liu Y, Wang M, Sun QY, Hu JY, Bao N, Xiao PX, Sun HJ, Han ZJ, Zhang JR. Cichoric acid ameliorates sepsis-induced acute kidney injury by inhibiting M1 macrophage polarization. Eur J Pharmacol. 2024;976:176696. doi: 10.1016/j.ejphar.2024.176696. PubMed DOI

Zhang L, Zhang G, Mao W, Sun S, Tao S, Gao Y, Zhang N, Jiang G, Chen M, Lu X, Chen S. Xuebijing injection alleviates septic acute kidney injury by modulating inflammation, mitochondrial dysfunction, and endoplasmic reticulum stress. Ren Fail. 2025;47:2483986. doi: 10.1080/0886022X.2025.2483986. PubMed DOI PMC

Yuan LL, Cao CY. Rehmannioside A Inhibits TRAF6/MAPK Pathway and Improves Psoriasis by Interfering with the Interaction of HaCaT Cells with IL-17A. Clin Cosmet Investig Dermatol. 2023;16:2585–2596. doi: 10.2147/CCID.S430621. PubMed DOI PMC

Sun M, Shen X, Ma Y. Rehmannioside A attenuates cognitive deficits in rats with vascular dementia (VD) through suppressing oxidative stress, inflammation and apoptosis. Biomed Pharmacother. 2019;120:109492. doi: 10.1016/j.biopha.2019.109492. PubMed DOI

Xiao S, Wang C, Yang Q, Xu H, Lu J, Xu K. Rea regulates microglial polarization and attenuates neuronal apoptosis via inhibition of the NF-κB and MAPK signalings for spinal cord injury repair. J Cell Mol Med. 2021;25:1371–1382. doi: 10.1111/jcmm.16220. PubMed DOI PMC

Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003;31:1250–1256. doi: 10.1097/01.CCM.0000050454.01978.3B. PubMed DOI

Wang J, Luo M, Shen J, Liu Z, Chen Y, Luo J, Zeng Z, Deng D, Xiao J. Bakuchiol from Psoralea corylifolia L. Ameliorates acute kidney injury and improves survival in experimental polymicrobial sepsis. International immunopharmacology. 2020;89:107000. doi: 10.1016/j.intimp.2020.107000. PubMed DOI

Kumar S, Ingle H, Prasad DV, Kumar H. Recognition of bacterial infection by innate immune sensors. Crit Rev Microbiol. 2013;39:229–246. doi: 10.3109/1040841X.2012.706249. PubMed DOI

Ciuffoli E, Troìa R, Bulgarelli C, Pontiero A, Buzzurra F, Giunti M. New-onset organ dysfunction as a screening tool for the identification of sepsis and outcome prediction in dogs with systemic inflammation. Front Vet Sci. 2024;11:1369533. doi: 10.3389/fvets.2024.1369533. PubMed DOI PMC

Xia Y, Zhang W, He K, Bai L, Miao Y, Liu B, Zhang X, Jin S, Wu Y. Hydrogen sulfide alleviates lipopolysaccharide-induced myocardial injury through TLR4-NLRP3 pathway. Physiol Res. 2023;72:15–25. doi: 10.33549/physiolres.934928. PubMed DOI PMC

Cold F, Schiødt FV, Pott FC, Strandkjær N, Christensen E. Sepsis-related Organ Failure Assessment Score is a strong predictor of survival in acute-on-chronic liver failure. Dan Med J. 2019:66. PubMed

Klementa V, Petejova N, Zadrazil J, Horak P, Proskova J, Langova K, Klementova O, Kanova M, Martinek A, Sigutova R, Stejskal D. Prediction of acute kidney injury development in critically ill septic patients based on NGAL determination. Physiol Res. 2024;73:1001–1011. doi: 10.33549/physiolres.935336. PubMed DOI PMC

Shou DW, Yu ZL, Meng JB, Lai ZZ, Pang LS, Dai MH, Yang X, Tu YX. Panax notoginseng alleviates sepsis-induced acute kidney injury by reducing inflammation in rats. Evid Based Complement Alternat Med. 2022;2022:9742169. doi: 10.1155/2022/9742169. PubMed DOI PMC

Ren Q, Guo F, Tao S, Huang R, Ma L, Fu P. Flavonoid fisetin alleviates kidney inflammation and apoptosis via inhibiting Src-mediated NF-κB p65 and MAPK signaling pathways in septic AKI mice. Biomed Pharmacother. 2020;122:109772. doi: 10.1016/j.biopha.2019.109772. PubMed DOI

Xia YM, Guan YQ, Liang JF, Wu WD. TAK-242 improves sepsis-associated acute kidney injury in rats by inhibiting the TLR4/NF-κB signaling pathway. Ren Fail. 2024;46:2313176. doi: 10.1080/0886022X.2024.2313176. PubMed DOI PMC

Shou DW, Li YR, Xu XJ, Dai MH, Zhang W, Yang X, Tu YX. Parthenolide attenuates sepsis-induced acute kidney injury in rats by reducing inflammation. Evid Based Complement Alternat Med. 2023;2023:8759766. doi: 10.1155/2023/8759766. PubMed DOI PMC

Dellepiane S, Marengo M, Cantaluppi V. Detrimental cross-talk between sepsis and acute kidney injury: new pathogenic mechanisms, early biomarkers and targeted therapies. Crit Care. 2016;20:61. doi: 10.1186/s13054-016-1219-3. PubMed DOI PMC

Hu W, Zou L, Yu N, Wu Z, Yang W, Wu T, Liu Y, Pu Y, Jiang Y, Zhang J, Zhu H, Cheng F, Feng S. Catalpol rescues LPS-induced cognitive impairment via inhibition of NF-κb-regulated neuroinflammation and up-regulation of TrkB-mediated BDNF secretion in mice. J Ethnopharmacol. 2024;319:117345. doi: 10.1016/j.jep.2023.117345. PubMed DOI

Han T, Jiang Y, Ge W, Lu Y, Liu R, Sun Z. 2,5-Dihydroxyacetophenone attenuates acute kidney injury induced by intra-abdominal infection in rats. Nephrology (Carlton) 2024;29:636–644. doi: 10.1111/nep.14335. PubMed DOI

Ban KY, Nam GY, Kim D, Oh YS, Jun HS. Prevention of LPS-Induced Acute Kidney Injury in Mice by Bavachin and Its Potential Mechanisms. Antioxidants (Basel) 2022:11. doi: 10.3390/antiox11112096. PubMed DOI PMC

Ranneh Y, Mahmoud AM, Fadel A, Albujja M, Akim AM, Hamid HA, Khazaai H. Acute Inflammation and Oxidative Stress Induced by Lipopolysaccharide and the Ameliorative Effect of Stingless Bee Honey. Comb Chem High Throughput Screen. 2021;24:744–757. doi: 10.2174/1386207323999200918152111. PubMed DOI

Li H, Ren Q, Hu Y, Guo F, Huang R, Lin L, Tan Z, Ma L, Fu P. SKLB023 protects against inflammation and apoptosis in sepsis-associated acute kidney injury via the inhibition of toll-like receptor 4 signaling. International immunopharmacology. 2024;139:112668. doi: 10.1016/j.intimp.2024.112668. PubMed DOI

Koo JH, Yu HC, Nam S, Kim DC, Lee JH. Casein Kinase 2 Alpha Inhibition Protects against Sepsis-Induced Acute Kidney Injury. Int J Mol Sci. 2023:24. doi: 10.3390/ijms24129783. PubMed DOI PMC

Sun S, Wang J, Wang J, Wang F, Yao S, Xia H. Maresin 1 Mitigates Sepsis-Associated Acute Kidney Injury in Mice via Inhibition of the NF-κB/STAT3/MAPK Pathways. Frontiers in pharmacology. 2019;10:1323. doi: 10.3389/fphar.2019.01323. PubMed DOI PMC

Wang Y, Cui C, Zhao W, Tian X, Liu P, Wei L, Zhu Z, Liu M, Fu R, Jia L. WIP1-mediated regulation of p38 MAPK signaling attenuates pyroptosis in sepsis-associated acute kidney injury. Immunobiology. 2024;229:152832. doi: 10.1016/j.imbio.2024.152832. PubMed DOI