Journal of Shanghai Jiao Tong University (Medical Science) >

2023 , Vol. 43 >Issue 1: 8 - 19

DOI: https://doi.org/10.3969/j.issn.1674-8115.2023.01.002

Basic research

Preventive effect of icariin on transition from acute kidney injury to chronic kidney disease in mouse model

  • Lin XIE ,
  • Ye CHENG ,
  • Qimin ZHENG ,
  • Xi ZHANG ,
  • Lili FU ,
  • Min CHEN ,
  • Yi WANG ,
  • Changlin MEI ,
  • Jingyuan XIE ,
  • Xiangchen GU
Expand
  • 1.Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
    2.Department of Nephrology, Yueyang Hospital of Integrated Traditional and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
    3.Department of Nephrology, The Second Affiliated Hospital of Naval Medical University (Shanghai Changzheng Hospital), Shanghai 200003, China
GU Xiangchen, E-mail: gettygugu@126.com.

Received date: 2022-04-29

  Accepted date: 2022-12-16

  Online published: 2023-01-28

Supported by

National Natural Science Foundation of China(81774106);Shanghai Pujiang Talent Program(18PJD049);Shanghai Jiao Tong University School of Medicine “Integrated Traditional Chinese and Western Medicine Research Platform”(2022zxy003);Program of Yueyang Hospital of Integrated Traditional and Western Medicine, Shanghai University of Traditional Chinese Medicine(2021yyjm01)

Fold

Abstract

Objective ·To investigate the effect of icariin on the transition from acute kidney disease (AKI) to chronic kidney disease (CKD) in mice and the possible mechanism. Methods ·C57BL/6 mice were intraperitoneally injected with aristolochic acid for 2 weeks to mimic AKI to CKD transition. Icariin was intragastrically administered for 2 or 5 weeks at the end of 2 weeks of aristolochic acid injection or 1 week before modeling. The renal function and pathological injury of the mice were monitored. The mitochondrial structure of renal tubular epithelial cells was observed by transmission electron microscopy. The indexes related to fatty acid oxidative metabolic pathway, fibrosis, and inflammation were detected by quantitative PCR (qPCR) and immunohistochemical staining. The rat renal fibroblast cell line and the rat renal tubular epithelial cell lines were co-cultured in Transwell cell chambers to simulate the interaction between the two types of cells. The renal tubular epithelial cells were pretreated with icariin for 1 h, and then treated with aristolochic acid for 24 h. After removing the two drugs, the renal tubular epithelial cells and the fibroblasts were co-cultured for 24 h. The mRNA or protein expression levels of peroxisome proliferator-activated receptor α (Ppara), pro-fibrotic factors, inflammatory factors, activated caspase-3 (cleaved caspase-3), and extracellular matrix-associated genes in renal fibroblasts were detected by qPCR or Western blotting. The renal tubular epithelial cells were transfected with Ppara-siRNA to observe the expression changes of cleaved caspase-3 and the related indicators of mitochondrial fatty acid oxidative metabolism in the downstream of PPARα after icariin intervention prior to aristolochic acid. Results ·Compared with the control group, the serum creatinine and urea nitrogen levels of the mice injected with aristolochic acid only were significantly higher, with a large number of inflammatory cells infiltrating into the kidney and serious renal tubular injury at the end of 2 weeks of aristolochic acid injection and 2 weeks after the last injection (4 weeks). The renal function was significantly improved, and the pathological damage was attenuated in the mice pretreated with icariin. After 4 weeks of modeling, the mitochondrial structure of renal tubular epithelial cells was seriously damaged in the aristolochic acid group, and the mRNA levels of fatty acid oxidative metabolic pathway-related genes were significantly downregulated, compared to the control group, accompanied by macrophage infiltration and renal fibrosis. Icariin pretreatment attenuated these damages generated by aristolochic acid. The serum creatinine and urea nitrogen levels, renal pathological injury, and fibrotic markers of the mice treated with icariin at the end of 2 weeks of aristolochic acid injection showed no difference from the aristolochic acid group. In the in vitro experiments, aristolochic acid treatment suppressed Ppara mRNA expression and elevated cleaved caspase-3, inflammatory factors, and pro-fibrotic factors in renal tubular epithelial cells. It also upregulated the expression of extracellular matrix-related genes in co-cultured renal fibroblasts. In contrast, icariin pretreatment abrogated the changes caused by aristolochic acid. The knockdown of Ppara by siRNA in renal tubular epithelial cells removed the preventive effects of icariin on aristolochic acid inhibiting fatty acid oxidative metabolism and promoting cell apoptosis. Conclusion ·Icariin prevents AKI to CKD transition induced by aristolochic acid in mice. It may play its protective role by improving the mitochondrial fatty acid oxidative metabolic pathway, especially through PPARα, in renal tubular epithelial cells.

Key words： icariin; acute kidney injury (AKI); chronic kidney disease (CKD); mitochondria; fatty acid oxidation; renal tubule epithelial cell

Cite this article

Lin XIE , Ye CHENG , Qimin ZHENG , Xi ZHANG , Lili FU , Min CHEN , Yi WANG , Changlin MEI , Jingyuan XIE , Xiangchen GU . Preventive effect of icariin on transition from acute kidney injury to chronic kidney disease in mouse model[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023 , 43(1) : 8 -19 . DOI: 10.3969/j.issn.1674-8115.2023.01.002

References

1 KURZHAGEN J T, DELLEPIANE S, CANTALUPPI V, et al. AKI: an increasingly recognized risk factor for CKD development and progression[J]. J Nephrol, 2020, 33(6): 1171-1187.
2 BUCALOIU I D, KIRCHNER H L, NORFOLK E R, et al. Increased risk of death and de novo chronic kidney disease following reversible acute kidney injury[J]. Kidney Int, 2012, 81(5): 477-485.
3 HE L Y, WEI Q Q, LIU J, et al. AKI on CKD: heightened injury, suppressed repair, and the underlying mechanisms[J]. Kidney Int, 2017, 92(5): 1071-1083.
4 VENKATACHALAM M A, WEINBERG J M, KRIZ W, et al. Failed tubule recovery, AKI-CKD transition, and kidney disease progression[J]. J Am Soc Nephrol, 2015, 26(8): 1765-1776.
5 顾向晨, 张红利, 程烨, 等. 淫羊藿苷对血管紧张素Ⅱ诱导肾纤维化的保护作用研究[J]. 上海医学, 2020, 43(10): 611-617.
5 GU X C, ZHANG H L, CHENG Y, et al. Protective effect of icariin on angiotensin Ⅱ induced renal fibrosis[J]. Shanghai Medical Journal, 2020, 43(10): 611-617.
6 XIE L, FU L L, MEI C L, et al. Icariin attenuates renal interstitial fibrosis through G protein-coupled estrogen receptor in a UUO murine model[J]. Am J Transl Res, 2022, 14(3): 1567-1577.
7 MA P, ZHANG S, SU X L, et al. Protective effects of icariin on cisplatin-induced acute renal injury in mice[J]. Am J Transl Res, 2015, 7(10): 2105-2114.
8 JADOT I, COLOMBARO V, MARTIN B, et al. Restored nitric oxide bioavailability reduces the severity of acute-to-chronic transition in a mouse model of aristolochic acid nephropathy[J]. PLoS One, 2017, 12(8): e0183604.
9 HUANG L H, SCARPELLINI A, FUNCK M, et al. Development of a chronic kidney disease model in C57BL/6 mice with relevance to human pathology[J]. Nephron Extra, 2013, 3(1): 12-29.
10 FU Y, TANG C Y, CAI J, et al. Rodent models of AKI-CKD transition[J]. Am J Physiol Renal Physiol, 2018, 315(4): F1098-F1106.
11 SHIMIZU A, MASUDA Y, MORI T, et al. Vascular endothelial growth factor165 resolves glomerular inflammation and accelerates glomerular capillary repair in rat anti-glomerular basement membrane glomerulonephritis[J]. J Am Soc Nephrol, 2004, 15(10): 2655-2665.
12 TAKAORI K, NAKAMURA J, YAMAMOTO S, et al. Severity and frequency of proximal tubule injury determines renal prognosis[J]. J Am Soc Nephrol, 2016, 27(8): 2393-2406.
13 GU X C, YANG H L, SHENG X, et al. Kidney disease genetic risk variants alter lysosomal β-mannosidase (MANBA) expression and disease severity[J]. Sci Transl Med, 2021, 13(576): eaaz1458.
14 CHAWLA L S, EGGERS P W, STAR R A, et al. Acute kidney injury and chronic kidney disease as interconnected syndromes[J]. N Engl J Med, 2014, 371(1): 58-66.
15 HOSTE E A J, KELLUM J A, SELBY N M, et al. Global epidemiology and outcomes of acute kidney injury[J]. Nat Rev Nephrol, 2018, 14(10): 607-625.
16 HORNE K L, PACKINGTON R, MONAGHAN J, et al. Three-year outcomes after acute kidney injury: results of a prospective parallel group cohort study[J]. BMJ Open, 2017, 7(3): e015316.
17 YU S M W, BONVENTRE J V. Acute kidney injury and maladaptive tubular repair leading to renal fibrosis[J]. Curr Opin Nephrol Hypertens, 2020, 29(3): 310-318.
18 KANG H M, AHN S H, CHOI P, et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development[J]. Nat Med, 2015, 21(1): 37-46.
19 WANG M, GAO H Y, LI W H, et al. Icariin and its metabolites regulate lipid metabolism: from effects to molecular mechanisms[J]. Biomed Pharmacother, 2020, 131: 110675.
20 WU B, FENG J Y, YU L M, et al. Icariin protects cardiomyocytes against ischaemia/reperfusion injury by attenuating sirtuin 1-dependent mitochondrial oxidative damage[J]. Br J Pharmacol, 2018, 175(21): 4137-4153.
21 PU L Y, MENG Q Y, LI S, et al. Icariin arrests cell cycle progression and induces cell apoptosis through the mitochondrial pathway in human fibroblast-like synoviocytes[J]. Eur J Pharmacol, 2021, 912: 174585.
22 SONG Y H, CAI H, ZHAO Z M, et al. Icariin attenuated oxidative stress induced-cardiac apoptosis by mitochondria protection and ERK activation[J]. Biomed Pharmacother, 2016, 83: 1089-1094.
23 LI Y C, DING X S, LI H M, et al. Icariin attenuates high glucose-induced type Ⅳ collagen and fibronectin accumulation in glomerular mesangial cells by inhibiting transforming growth factor-β production and signalling through G protein-coupled oestrogen receptor 1[J]. Clin Exp Pharmacol Physiol, 2013, 40(9): 635-643.
24 PANT A, RONDINI E A, KOCAREK T A. Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells[J]. Toxicol Appl Pharmacol, 2019, 365: 61-70.
25 CHUNG K W, LEE E K, LEE M K, et al. Impairment of PPARα and the fatty acid oxidation pathway aggravates renal fibrosis during aging[J]. J Am Soc Nephrol, 2018, 29(4): 1223-1237.
26 LU Y F, XU Y Y, JIN F, et al. Icariin is a PPARα activator inducing lipid metabolic gene expression in mice[J]. Molecules, 2014, 19(11): 18179-18191.
Options
Outlines

/

〈 〉