Alpiniae oxyphyllae Fructus ameliorates renal lipid accumulation in diabetic kidney disease via activating PPARα

Abstract

Objective: To investigate the effects of Alpiniae oxyphyllae Fructus (AOF) on renal lipid deposition in diabetic kidney disease (DKD) and elucidate its molecular mechanisms.

Methods: The mechanism of AOF in treating DKD was explored by network pharmacological enrichment analysis, molecular docking, and molecular dynamics simulation. The effects of AOF on renal function and lipid deposition were assessed in a mouse model of DKD and high glucose-stressed HK-2 cells. Cell viability and lipid accumulation were detected by CCK8 and oil red O staining. The expressions of PPARα and fatty acid oxidation-related genes (ACOX1 and CPT1A) were detected by quantitative RT-PCR, Western blot, and immunofluorescence. Furthermore, PPARα knockdown was performed to examine the molecular mechanism of AOF in treating DKD.

Results:Network pharmacological enrichment analysis, molecular docking, and molecular dynamics simulation showed that the active compounds in AOF targeted PPARα and thus transcriptionally regulated ACOX1 and CPT1A. AOF lowered blood glucose, improved dyslipidemia, and attenuated renal injury in DKD mice. AOF-containing serum accentuated high glucose-induced decrease in cell viability and ameliorated lipid accumulation. Additionally, it significantly upregulated the expression of PPARα, ACOX1, and CPT1A in both in vivo and in vitro experiments, which was reversed by PPARα knockdown.

Conclusions: AOF may promote fatty acid oxidation via PPARα to ameliorate renal lipid deposition in DKD.

Keywords

Diabetic kidney disease / Alpiniae oxyphyllae Fructus / Natural medicine / Lipid accumulation / PPARα / Fatty acid oxidation

Conflict of interest statement

The authors declare that there is no conflict of interest.

Funding

This work was supported by the grants from National Natural Science Foundation of China (No. 82174334), and 2022 Postgraduate Innovation Research Projects in Hainan Province (No. Qhys2022-273).

Data availability statement

The data supporting the findings of this study are available from the corresponding authors upon request.

Authors’ contributions

Conceptualization and design were performed by YQX, ZJY, and MX. Data collection, analysis and interpretation were done by ZJY, LZ, XYH, YK, SML, and TPM. Funding acquisition was from YQX. The first draft of the manuscript was written by ZJY and LZ. The previous version and revised version of the manuscript were commented by ZJY, LZ, YQX, MX and XYH. The final manuscript was read and approved by YQX, MX, ZJY and LZ.

Publisher’s note

The Publisher of the Journal remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

[1] Naaman SC, Bakris GL. Diabetic nephropathy: Update on pillars of therapy slowing progression. Diabetes Care 2023; 46(9):1574-1586.

[2] Liu G, Li Y, Pan A, Hu Y, Chen S, Qian F, et al. Adherence to a healthy lifestyle in association with microvascular complications among adults with type 2 diabetes. JAMA Netw Open 2023; 6(1):e2252239.

[3] Pérez-Martí A, Ramakrishnan S, Li J, Dugourd A, Molenaar MR, De La Motte LR, et al. Reducing lipid bilayer stress by monounsaturated fatty acids protects renal proximal tubules in diabetes. Elife 2022;11:e74391.

[4] Lu J, Li XQ, Chen PP, Zhang JX, Li L, Wang GH, et al. Acetyl-CoA synthetase 2 promotes diabetic renal tubular injury in mice by rewiring fatty acid metabolism through SIRT1/ChREBP pathway. Acta Pharmacol Sin 2024; 45(2):366-377.

[5] Xu T, Lim YT, Chen L, Zhao H, Low JH, Xia Y, et al. A novel mechanism of monoethylhexyl phthalate in lipid accumulation via inhibiting fatty acid beta-oxidation on hepatic cells. Environ Sci Technol 2020; 54(24):15925-15934.

[6] Hu H, Li W, Hao Y, Peng Z, Zou Z, Liang W. Baicalin ameliorates renal fibrosis by upregulating CPT1α-mediated fatty acid oxidation in diabetic kidney disease. Phytomedicine 2024;122:155162.

[7] Selby NM, Taal MW. An updated overview of diabetic nephropathy: Diagnosis, prognosis, treatment goals and latest guidelines. Diabetes Obes Metab 2020;22Suppl 1:3-15.

[8] Hu Q, Chen Y, Deng X, Li Y, Ma X, Zeng J, et al. Diabetic nephropathy: Focusing on pathological signals, clinical treatment, and dietary regulation. Biomed Pharmacother 2023;159:114252.

[9] Zhang Z, Leng Y, Chen Z, Fu X, Liang Q, Peng X, et al. The efficacy and safety of Chinese herbal medicine as an add-on therapy for type 2 diabetes mellitus patients with carotid atherosclerosis: An updated meta-analysis of 27 randomized controlled trials. Front Pharmacol 2023;14:1091718.

[10] Yu SH, Kim HJ, Jeon SY, Kim MR, Lee BS, Lee JJ, et al. Anti-inflammatory and anti-nociceptive activities of Alpinia oxyphylla Miquel extracts in animal models. J Ethnopharmacol 2020;260:112985.

[11] Yan Z, Zhang L, Kang Y, Liu S, Li X, Li L, et al. Integrating serum pharmacochemistry and network pharmacology to explore potential compounds and mechanisms of Alpiniae oxyphyllae fructus in the treatment of cellular senescence in diabetic kidney disease. Front Med (Lausanne) 2024;11:1424644. doi: 10.3389/fmed.2024.1424644.

[12] NI Y, Yao Y, Wu S, Xie Y. Study on the protective mechanism of Yizhiren regulating lipid metabolism in mice with diabetic nephropathy. J Hainan Med Univ 2023; 29(11):801-807. doi: 10.13210/j.cnki.jhmu.20230329.001.

[13] Luan ZL, Zhang C, Ming WH, Huang YZ, Guan YF, Zhang XY. Nuclear receptors in renal health and disease. EBioMedicine 2022;76:103855.

[14] Chen L, Sha ML, Chen FT, Jiang CY, Li D, Xu CL, et al. Upregulation of KLF 14 expression attenuates kidney fibrosis by inducing PPARα-mediated fatty acid oxidation. Free Radic Biol Med 2023;195:132-144.

[15] Piret SE, Attallah AA, Gu X, Guo Y, Gujarati NA, Henein J, et al. Loss of proximal tubular transcription factor Krüppel-like factor 15 exacerbates kidney injury through loss of fatty acid oxidation. Kidney Int 2021; 100(6):1250-1267.

[16] Yan Z, Kang Y, Liu S, Chen B, Ma T, Xiao M, et al. Alpiniae oxyphyllae fructus ameliorates diabetic kidney disease through activation of PPARα-mediated autophagy. J Hainan Med Univ 2024; 30(17):1281-1289. doi: 10.13210/j.cnki.jhmu.20240518.001.

[17] Cole JB, Florez JC. Genetics of diabetes mellitus and diabetes complications. Nat Rev Nephrol 2020; 16(7):377-390.

[18] Dejenie TA, Abebe EC, Mengstie MA, Seid MA, Gebeyehu NA, Adella GA, et al. Dyslipidemia and serum cystatin C levels as biomarker of diabetic nephropathy in patients with type 2 diabetes mellitus. Front Endocrinol (Lausanne) 2023;14:1124367.

[19] Wu M, Yang Z, Zhang C, Shi Y, Han W, Song S, et al. Inhibition of NLRP 3 inflammasome ameliorates podocyte damage by suppressing lipid accumulation in diabetic nephropathy. Metabolism 2021;118:154748.

[20] Ding T, Wang S, Zhang X, Zai W, Fan J, Chen W, et al. Kidney protection effects of dihydroquercetin on diabetic nephropathy through suppressing ROS and NLRP 3 inflammasome. Phytomedicine 2018;41:45-53.

[21] Oshima M, Shimizu M, Yamanouchi M, Toyama T, Hara A, Furuichi K, et al. Trajectories of kidney function in diabetes: A clinicopathological update. Nat Rev Nephrol 2021; 17(11):740-750.

[22] Zhang Q, Zheng Y, Hu X, Hu X, Lv W, Lv D, et al. Ethnopharmacological uses, phytochemistry, biological activities, and therapeutic applications of Alpinia oxyphylla Miquel: A review. J Ethnopharmacol 2018;224:149-168.

[23] Cai P, Wu Z, Huang W, Niu Q, Zhu Y, Yin D. Suoquan pill for the treatment of diabetic nephropathy: A protocol for systematic review and meta-analysis. Medicine (Baltimore) 2021; 100(17):e25613.

[24] Yin DH, Zhu Y, Ni YL, Yao Y, Lin D, Xie Y. Clinical effect of Suoquan Yishen recipe on type 2 diabetic nephropathy. Chin J Gerontol 2019; 39(9):2091-2092.

[25] Chen SJ, Lv LL, Liu BC, Tang RN. Crosstalk between tubular epithelial cells and glomerular endothelial cells in diabetic kidney disease. Cell Prolif 2020; 53(3):e12763.

[26] Xu F, Jiang H, Li X, Pan J, Li H, Wang L, et al. Discovery of PRDM16-mediated TRPA 1 induction as the mechanism for low tubulo-interstitial fibrosis in diabetic kidney disease. Adv Sci (Weinh) 2024; 11(7):e2306704.

[27] Kamel FO, Shagroud O, Ahmad MA, Abd El-Aziz GS, Burzangi AS, Bakhshwin D, et al. Agmatine ameliorates diabetes type 2-induced nephropathy in rats. Asian Pac J Trop Biomed 2024; 14(1):8-16.

[28] Yang M, Luo S, Yang J, Chen W, He L, Liu D, et al. Lipid droplet-mitochondria coupling: A novel lipid metabolism regulatory hub in diabetic nephropathy. Front Endocrinol (Lausanne) 2022;13:1017387.

[29] Thongnak L, Pongchaidecha A, Lungkaphin A. Renal lipid metabolism and lipotoxicity in diabetes. Am J Med Sci 2020; 359(2):84-99.

[30] Mitrofanova A, Merscher S, Fornoni A. Kidney lipid dysmetabolism and lipid droplet accumulation in chronic kidney disease. Nat Rev Nephrol 2023; 19(10):629-645.

[31] Cao Z, Zhao H, Fan J, Shen Y, Han L, Jing G, et al. Simultaneous blockade of VEGF-B and IL-17A ameliorated diabetic kidney disease by reducing ectopic lipid deposition and alleviating inflammation response. Cell Death Discov 2023; 9(1):8.

[32] Da J, Xu Y, Tan Y, Zhang J, Yu J, Zhao J, et al. Central administration of Dapagliflozin alleviates a hypothalamic neuroinflammatory signature and changing tubular lipid metabolism in type 2 diabetic nephropathy by upregulating MCPIP1. Biomed Pharmacother 2023;168:115840.

[33] Lin Y, Wang Y, Li PF. PPARα: An emerging target of metabolic syndrome, neurodegenerative and cardiovascular diseases. Front Endocrinol (Lausanne) 2022;13:1074911.

[34] Kersten S. Integrated physiology and systems biology of PPARα. Mol Metab 2014; 3(4):354-371.

[35] Tahri-Joutey M, Andreoletti P, Surapureddi S, Nasser B, Cherkaoui-Malki M, Latruffe N. Mechanisms mediating the regulation of peroxisomal fatty acid beta-oxidation by PPARα. Int J Mol Sci 2021; 22(16):8969.

[36] Pawlak M, Lefebvre P, Staels B. Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J Hepatol 2015; 62(3):720-733.

[37] Chen Q, Xie C, Tang K, Luo M, Zhang Z, Jin Y, et al. The E3 ligase Trim 63 promotes podocyte injury and proteinuria by targeting PPARα to inhibit fatty acid oxidation. Free Radic Biol Med 2023; 209(Pt 1):40-54.

[38] Zhou Y, Kong X, Zhao P, Yang H, Chen L, Miao J, et al. Peroxisome proliferator-activated receptor-α is renoprotective in doxorubicin-induced glomerular injury. Kidney Int 2011; 79(12):1302-1311.

[39] Kouroumichakis I, Papanas N, Zarogoulidis P, Liakopoulos V, Maltezos E, Mikhailidis DP. Fibrates: Therapeutic potential for diabetic nephropathy? Eur J Intern Med 2012; 23(4):309-316.

[40] Chen J, Chen J, Fu H, Li Y, Wang L, Luo S, et al. Hypoxia exacerbates nonalcoholic fatty liver disease via the HIF-2α/PPARα pathway. Am J Physiol Endocrinol Metab 2019; 317(4):E710-E722.

[41] Fang X, Du Z, Duan C, Zhan S, Wang T, Zhu M, et al. Beinaglutide shows significantly beneficial effects in diabetes/obesity-induced nonalcoholic steatohepatitis in ob/ob mouse model. Life Sci 2021;270:118966.

[42] Chen N, Mu L, Yang Z, Du C, Wu M, Song S, et al. Carbohydrate response element-binding protein regulates lipid metabolism via mTOR complex 1 in diabetic nephropathy. J Cell Physiol 2021; 236(1):625-640.

[43] Xiang J, Zhang H, Zhou X, Wang D, Chen R, Tan W, et al. Atorvastatin restores PPARα inhibition of lipid metabolism disorders by downregulating miR-21 expression to improve mitochondrial function and alleviate diabetic nephropathy progression. Front Pharmacol 2022;13:819787.