Qufeng Tongluo Decoction Decreased Proteinuria in Diabetic Mice by Protecting Podocytes Via Promoting Autophagy

Overview

Journal J Tradit Complement Med

Specialty Rehabilitation Medicine

Date 2024 May 6

PMID 38707926

Authors

Boran Ni

Yao Xiao

Ruojun Wei

Weijing Liu

Liwei Zhu

Yifan Liu

Zhichao Ruan

Jiamu Li

Shidong Wang

Jinxi Zhao

Weijun Huang

Affiliations

Soon will be listed here.

Abstract

Background: Diabetic kidney disease (DKD) is one of diabetic complications, which has become the leading cause of end-stage kidney disease. In addition to angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker(ACEI/ARB) and sodium-glucose cotransporter-2 inhibitor (SGLT2i), traditional Chinese medicine (TCM) is an effective alternative treatment for DKD. In this study, the effect of Qufeng Tongluo (QFTL) decoction in decreasing proteinuria has been observed and its mechanism has been explored based on autophagy regulation in podocyte.

Methods: In vivo study, db/db mice were used as diabetes model and db/m mice as blank control. Db/db mice were treated with QFTL decoction, rapamycin, QFTL + 3-Methyladenine (3-MA), trehalose, chloroquine (CQ) and QFTL + CQ. Mice urinary albumin/creatinine (UACR), nephrin and autophagy related proteins (LC3 and p62) in kidney tissue were detected after intervention of 9 weeks. Transcriptomics was operated with the kidney tissue from model group and QFTL group. In vitro study, mouse podocyte clone-5 (MPC-5) cells were stimulated with hyperglycemic media (30 mmol/L glucose) or cultured with normal media. High-glucose-stimulated MPC-5 cells were treated with QFTL freeze-drying powder, rapamycin, CQ, trehalose, QFTL+3-MA and QFTL + CQ. Cytoskeletal actin, nephrin, ATG-5, ATG-7, Beclin-1, cathepsin L and cathepsin B were assessed. mRFP-GFP-LC3 was established by stubRFP-sensGFP-LC3 lentivirus transfection.

Results: QFTL decoction decreased the UACR and increased the nephrin level in kidney tissue and high-glucose-stimulated podocytes. Autophagy inhibitors, including 3-MA and chloroquine blocked the effects of QFTL decoction. Further study showed that QFTL decoction increased the LC3 expression and relieved p62 accumulation in podocytes of db/db mice. In high-glucose-stimulated MPC-5 cells, QFTL decoction rescued the inhibited LC3 and promoted the expression of ATG-5, ATG-7, and Beclin-1, while had no effect on the activity of cathepsin L and cathepsin B. Results of transcriptomics also showed that 51 autophagy related genes were regulated by QFTL decoction, including the genes of ATG10, SCOC, ATG4C, AMPK catalytic subunit, PI3K catalytic subunit, ATG3 and DRAM2.

Conclusion: QFTL decoction decreased proteinuria and protected podocytes in db/db mice by regulating autophagy.

Citing Articles

Novel Insights into Diabetic Kidney Disease.

Mlynarska E, Bulawska D, Czarnik W, Hajdys J, Majchrowicz G, Prusinowski F Int J Mol Sci. 2024; 25(18).

PMID: 39337706 PMC: 11432709. DOI: 10.3390/ijms251810222.

References

Huang W, Fu Q, Xiao Y, Gong Q, Wu W, Shen Z . Effect of Qufengtongluo Decoction on PI3K/Akt Signaling Pathway in the Kidney of Type 2 Diabetes Mellitus Rat (GK Rat) with Diabetic Nephropathy. Evid Based Complement Alternat Med. 2018; 2018:8421979. PMC: 5820584. DOI: 10.1155/2018/8421979. View

Levine B, Kroemer G . Biological Functions of Autophagy Genes: A Disease Perspective. Cell. 2019; 176(1-2):11-42. PMC: 6347410. DOI: 10.1016/j.cell.2018.09.048. View

Perlman A, Chevalier J, Wilkinson P, Liu H, Parker T, Levine D . Serum Inflammatory and Immune Mediators Are Elevated in Early Stage Diabetic Nephropathy. Ann Clin Lab Sci. 2015; 45(3):256-63. View

Li Y, Zhou D, Ren Y, Zhang Z, Guo X, Ma M . Mir223 restrains autophagy and promotes CNS inflammation by targeting ATG16L1. Autophagy. 2018; 15(3):478-492. PMC: 6351131. DOI: 10.1080/15548627.2018.1522467. View

Dong Z, Dai H, Gao Y, Feng Z, Liu W, Liu F . Inhibition of the Wnt/β-catenin signaling pathway reduces autophagy levels in complement treated podocytes. Exp Ther Med. 2021; 22(1):737. PMC: 8138266. DOI: 10.3892/etm.2021.10169. View

Li Y, Hu Q, Li C, Liang K, Xiang Y, Hsiao H . PTEN-induced partial epithelial-mesenchymal transition drives diabetic kidney disease. J Clin Invest. 2019; 129(3):1129-1151. PMC: 6391108. DOI: 10.1172/JCI121987. View

Tagawa A, Yasuda M, Kume S, Yamahara K, Nakazawa J, Chin-Kanasaki M . Impaired Podocyte Autophagy Exacerbates Proteinuria in Diabetic Nephropathy. Diabetes. 2015; 65(3):755-67. DOI: 10.2337/db15-0473. View

Tuttle K, Bakris G, Bilous R, Chiang J, de Boer I, Goldstein-Fuchs J . Diabetic kidney disease: a report from an ADA Consensus Conference. Diabetes Care. 2014; 37(10):2864-83. PMC: 4170131. DOI: 10.2337/dc14-1296. View

Dhanasekaran M, Narayanan S, Mastoris I, Mehta S . Canagliflozin-associated severe hyponatremia: a rare and potentially adverse effect?. Endocrinol Diabetes Metab Case Rep. 2022; 2022. PMC: 9002205. DOI: 10.1530/EDM-21-0035. View

10.

Deng F, Ma Y, Liang L, Zhang P, Feng J . The pro-apoptosis effect of sinomenine in renal carcinoma via inducing autophagy through inactivating PI3K/AKT/mTOR pathway. Biomed Pharmacother. 2017; 97:1269-1274. DOI: 10.1016/j.biopha.2017.11.064. View

11.

Wang H, Li J, Han Q, Yang F, Xiao Y, Xiao M . IL-12 Influence mTOR to Modulate CD8 T Cells Differentiation through T-bet and Eomesodermin in Response to Invasive Pulmonary Aspergillosis. Int J Med Sci. 2017; 14(10):977-983. PMC: 5599921. DOI: 10.7150/ijms.20212. View

12.

Kelley J, Strum M, Riche D, Chandler A . Sodium Glucose Transporter 2 Inhibitors and Diabetic Ketoacidosis in Three Patients with Diabetes: Underlying Causation. J Pharmacol Pharmacother. 2017; 8(3):137-139. PMC: 5642130. DOI: 10.4103/jpp.JPP_20_17. View

13.

Gill H, Kaur P, Mahendru S, Mithal A . Adverse Effect Profile and Effectiveness of Sodium Glucose Co-transporter 2 Inhibitors (SGLT2i) - A Prospective Real-world Setting Study. Indian J Endocrinol Metab. 2019; 23(1):50-55. PMC: 6446693. DOI: 10.4103/ijem.IJEM_566_18. View

14.

Qian C, Lu J, Che X, Min L, Wang M, Song A . P2X7R/AKT/mTOR signaling mediates high glucose-induced decrease in podocyte autophagy. Free Radic Biol Med. 2023; 204:337-346. DOI: 10.1016/j.freeradbiomed.2023.05.015. View

15.

Yi M, Zhang L, Liu Y, Livingston M, Chen J, Nahman Jr N . Autophagy is activated to protect against podocyte injury in adriamycin-induced nephropathy. Am J Physiol Renal Physiol. 2017; 313(1):F74-F84. PMC: 5538842. DOI: 10.1152/ajprenal.00114.2017. View

16.

Zhong Y, Jin R, Luo R, Liu J, Ren L, Zhang Y . Diosgenin Targets CaMKK2 to Alleviate Type II Diabetic Nephropathy through Improving Autophagy, Mitophagy and Mitochondrial Dynamics. Nutrients. 2023; 15(16). PMC: 10459415. DOI: 10.3390/nu15163554. View

17.

Tan S, Liu J, Fang Y, Hedlund B, Lian Z, Huang L . Insights into ecological role of a new deltaproteobacterial order Candidatus Acidulodesulfobacterales by metagenomics and metatranscriptomics. ISME J. 2019; 13(8):2044-2057. PMC: 6776010. DOI: 10.1038/s41396-019-0415-y. View

18.

Wada J, Makino H . Innate immunity in diabetes and diabetic nephropathy. Nat Rev Nephrol. 2015; 12(1):13-26. DOI: 10.1038/nrneph.2015.175. View

19.

Zhu Z, Song K, Huang W, Li H, Yang H, Bai Y . Si-Miao-Yong-An (SMYA) Decoction May Protect the Renal Function Through Regulating the Autophagy-Mediated Degradation of Ubiquitinated Protein in an Atherosclerosis Model. Front Pharmacol. 2020; 11:837. PMC: 7343850. DOI: 10.3389/fphar.2020.00837. View

20.

Yamahara K, Kume S, Koya D, Tanaka Y, Morita Y, Chin-Kanasaki M . Obesity-mediated autophagy insufficiency exacerbates proteinuria-induced tubulointerstitial lesions. J Am Soc Nephrol. 2013; 24(11):1769-81. PMC: 3810079. DOI: 10.1681/ASN.2012111080. View