https://doi.org/10.4081/ejh.2023.3648
The Qi-Bang-Yi-Shen formula ameliorates renal dysfunction and fibrosis in rats with diabetic kidney disease via regulating PI3K/AKT, ERK and PPARγ signaling pathways
Submitted: 12 January 2023
Accepted: 22 February 2023
Published: 1 March 2023
Accepted: 22 February 2023
Abstract Views: 1121
PDF: 675
HTML: 27
HTML: 27
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and a growing public health problem worldwide. Losartan potassium (Los), an angiotensin II receptor blocker, has been used to treat DKD clinically. Recently, multi-herbal formula has been shown to exhibit therapeutic activities in DKD in China. Thus, we aimed to explore the protective effects of combination of Los and Qi-Bang-Yi-Shen formula (QBF) on DKD rats. Streptozotocin (STZ) injection was used to establish a rat model of DKD. Next, the bloodurea nitrogen (BUN), creatinine (CRE) and uric acid (UA) levels were detected in serum samples from DKD rats. Hematoxylin and eosin (H&E), periodic Acid Schiff (PAS) and Masson staining were performed to observe glomerular injury and glomerular fibrosis in DKD rats. In this study, we found that QBF or Los treatment could decrease serum BUN, CRE, UA levels and reduce urine albumin-to-creatinine ratio (ACR) in DKD rats. Additionally, QBF or Los treatment obviously inhibited glomerular mesangial expansion and glomerular fibrosis, attenuated glomerular injury in kidney tissues of DKD rats. Moreover, QBF or Los treatment significantly reduced PI3K, AKT and ERK1/2 protein expressions, but increased PPARγ level in kidney tissues of DKD rats. As expected, combined treatment of QBF and Los could exert enhanced reno-protective effects compared with the single treatment. Collectively, combination of QBF and Los could ameliorate renal injury and fibrosis in DKD rats via regulating PI3K/AKT, ERK and PPARγ signaling pathways. These findings highlight the therapeutic potential of QBF to prevent DKD progression.
Sirhan W, Piran R. Current approaches in diabetes treatment and other strategies to reach normoglycemia. Curr Top Med Chem 2020;20:2922-44.
DOI: https://doi.org/10.2174/1568026620666200716113813
Chow J, Rahman J, Achermann JC, Dattani MT, Rahman S. Mitochondrial disease and endocrine dysfunction. Nat Rev Endocrinol 2017;13:92-104.
DOI: https://doi.org/10.1038/nrendo.2016.151
Lalla E, Papapanou PN. Diabetes mellitus and periodontitis: a tale of two common interrelated diseases. Nat Rev Endocrinol 2011;7:738-48.
DOI: https://doi.org/10.1038/nrendo.2011.106
Demir S, Nawroth PP, Herzig S, Ekim Üstünel B. Emerging targets in type 2 diabetes and diabetic complications. Adv Sci (Weinh) 2021;8:e2100275.
DOI: https://doi.org/10.1002/advs.202100275
Memon B AE. Stem cell therapy for diabetes: Beta cells versus pancreatic progenitors. Cells 2020;9:283.
DOI: https://doi.org/10.3390/cells9020283
Huang DD, Shi G, Jiang Y, Yao C, Zhu C. A review on the potential of Resveratrol in prevention and therapy of diabetes and diabetic complications. Biomed Pharmacother 2020;125:109767.
DOI: https://doi.org/10.1016/j.biopha.2019.109767
Lin YC, Chang YH, Yang SY, Wu KD, Chu TS. Update of pathophysiology and management of diabetic kidney disease. J Formos Med Assoc 2018;117:662-75.
DOI: https://doi.org/10.1016/j.jfma.2018.02.007
McKnight AJ, McKay GJ, Maxwell AP. Genetic and epigenetic risk factors for diabetic kidney disease. Adv Chronic Kidney Dis 2014;21:287-96.
DOI: https://doi.org/10.1053/j.ackd.2014.03.010
Umanath K, Lewis JB. Update on diabetic nephropathy: Core curriculum 2018. Am J Kidney Dis 2018;71:884-95.
DOI: https://doi.org/10.1053/j.ajkd.2017.10.026
Mauer M, Doria A. Uric acid and risk of diabetic kidney disease. J Nephrol 2020;33:995-9.
DOI: https://doi.org/10.1007/s40620-020-00796-z
Fioretto P, Zambon A, Rossato M, Busetto L, Vettor R. SGLT2 Inhibitors and the diabetic kidney. Diabetes Care 2016;39:S165-71.
DOI: https://doi.org/10.2337/dcS15-3006
Sarafidis PA, Ruilope LM. Aggressive blood pressure reduction and renin-angiotensin system blockade in chronic kidney disease: time for re-evaluation? Kidney Int 2014;85:536-46.
DOI: https://doi.org/10.1038/ki.2013.355
Kovarik JJ, Kaltenecker CC, Domenig O, Antlanger M, Poglitsch M, Kopecky C, et al. Effect of mineralocorticoid receptor antagonism and ACE Inhibition on angiotensin profiles in diabetic kidney disease: An exploratory study. Diabetes Ther 2021;12:2485-98.
DOI: https://doi.org/10.1007/s13300-021-01118-7
Ferrari R. RAAS inhibition and mortality in hypertension. Glob Cardiol Sci Pract 2013;2013:269-78.
DOI: https://doi.org/10.5339/gcsp.2013.34
Perico N, Ruggenenti P, Remuzzi G. Losartan in diabetic nephropathy. Expert Rev Cardiovasc Ther 2004;2:473-83.
DOI: https://doi.org/10.1586/14779072.2.4.473
Wu R, Wei F, Qu L, Bai L, Li J, Li F, et al. Effects of Keluoxin capsule combined with losartan potassium on diabetic kidney disease: study protocol for a randomized double-blind placebo-controlled multicenter clinical trial. Trials 2020;21:951.
DOI: https://doi.org/10.1186/s13063-020-04852-8
Cheng SY, Chou YH, Liao FL, Lin CC, Chang FC, Liu CH, et al. Losartan reduces ensuing chronic kidney disease and mortality after acute kidney injury. Sci Rep 2016;6:34265.
DOI: https://doi.org/10.1038/srep34265
Li P, Chen Y, Liu J, Hong J, Deng Y, Yang F, et al. Efficacy and safety of tangshen formula on patients with type 2 diabetic kidney disease: a multicenter double-blinded randomized placebo-controlled trial. PLoS One 2015;10:e0126027.
DOI: https://doi.org/10.1371/journal.pone.0126027
Tu X, Ye X, Xie C, Chen J, Wang F, Zhong S. Combination therapy with Chinese medicine and ACEI/ARB for the management of diabetic nephropathy: The promise in research fragments. Curr Vasc Pharmacol 2015;13:526-39.
DOI: https://doi.org/10.2174/1570161112666141014153410
Zhang HW, Lin ZX, Xu C, Leung C, Chan LS. Astragalus (a traditional Chinese medicine) for treating chronic kidney disease. Cochrane Database Syst Rev 2014;(10):CD008369.
DOI: https://doi.org/10.1002/14651858.CD008369.pub2
Wang L, Zhu JH, Jiang XD, Ma ZX, Tao JH. Preventive effects of the Rehmannia glutinosa Libosch and Cornus officinalis Sieb herb couple on chronic kidney disease rats via modulating the intestinal microbiota and enhancing the intestinal barrier. Front Pharmacol 2022;13:942032.
DOI: https://doi.org/10.3389/fphar.2022.942032
Xiaojia W, Jianchun L, Bingwen Z, Xingcan H, Yanmei D, Li W. Exploring the mechanism of Astragalus propinquus Schischkin and Panax Notoginseng (A&P) compounds in the treatment of renal fibrosis and chronic kidney disease based on integrated network analysis. Evid Based Complement Alternat Med 2022;2022:2646022.
DOI: https://doi.org/10.1155/2022/2646022
Su J, Zhang P, Zhang JJ, Qi XM, Wu YG, Shen JJ. Effects of total glucosides of paeony on oxidative stress in the kidney from diabetic rats. Phytomedicine 2010;17:254-60.
DOI: https://doi.org/10.1016/j.phymed.2009.07.005
Han F, Xia XX, Dou M, Wang YX, Xue WJ, Ding XM, et al. Arctigenin: A two-edged sword in ischemia/reperfusion induced acute kidney injury. Biomed Pharmacother 2018;103:1127-36.
DOI: https://doi.org/10.1016/j.biopha.2018.04.169
Jin D, Liu F, Yu M, Zhao Y, Yan G, Xue J, et al. Jiedu Tongluo Baoshen formula enhances podocyte autophagy and reduces proteinuria in diabetic kidney disease by inhibiting PI3K/Akt/mTOR signaling pathway. J Ethnopharmacol 2022;293:115246.
DOI: https://doi.org/10.1016/j.jep.2022.115246
Shen S, Huang J, Xu C, Shen Y, Jiang S, Li Y, et al. ERK modulates macrophage polarization and alters exosome miRNA expression in diabetic nephropathy. Clin Lab 2021;67:210314.
DOI: https://doi.org/10.7754/Clin.Lab.2021.210314
Yang J, Zhou Y, Guan Y. PPARγ as a therapeutic target in diabetic nephropathy and other renal diseases. Curr Opin Nephrol Hypertens 2012;21:97-105.
DOI: https://doi.org/10.1097/MNH.0b013e32834de526
Reidy K, Kang HM, Hostetter T, Susztak K. Molecular mechanisms of diabetic kidney disease. J Clin Invest 2014;124:2333-40.
DOI: https://doi.org/10.1172/JCI72271
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;17:740-50.
DOI: https://doi.org/10.1038/s41581-021-00462-y
Giralt-López A M-VdBM, Vergara A, García-Carro C, Seron D, Jacobs-Cachá C, Soler MJ. Revisiting experimental models of diabetic nephropathy. Int J Mol Sci 2020;21:3587.
DOI: https://doi.org/10.3390/ijms21103587
Fang Y, Chen B, Gong AY, Malhotra DK, Gupta R, Dworkin LD, et al. The ketone body β-hydroxybutyrate mitigates the senescence response of glomerular podocytes to diabetic insults. Kidney Int 2021;100:1037-53.
DOI: https://doi.org/10.1016/j.kint.2021.06.031
Tung CW, Hsu YC, Shih YH, Chang PJ, Lin CL. Glomerular mesangial cell and podocyte injuries in diabetic nephropathy. Nephrology (Carlton) 2018;23:S32-7.
DOI: https://doi.org/10.1111/nep.13451
Piao Y, Yin D. Mechanism underlying treatment of diabetic kidney disease using traditional Chinese medicine based on theory of Yin and Yang balance. J Tradit Chin Med 2018;38:797-802.
DOI: https://doi.org/10.1016/S0254-6272(18)30921-X
Zhang L, Shergis JL, Yang L, Zhang AL, Guo X, Zhang L, et al. Astragalus membranaceus (Huang Qi) as adjunctive therapy for diabetic kidney disease: An updated systematic review and meta-analysis. J Ethnopharmacol 2019;239:111921.
DOI: https://doi.org/10.1016/j.jep.2019.111921
Dai B, Wu Q, Zeng C, Zhang J, Cao L, Xiao Z, et al. The effect of Liuwei Dihuang decoction on PI3K/Akt signaling pathway in liver of type 2 diabetes mellitus (T2DM) rats with insulin resistance. J Ethnopharmacol 2016;192:382-9.
DOI: https://doi.org/10.1016/j.jep.2016.07.024
Lin X, Lei XQ, Yang JK, Jia J, Zhong X, Tan RZ, et al. Astragalus mongholicus Bunge and Panax notoginseng formula (A&P) improves renal mesangial cell damage in diabetic nephropathy by inhibiting the inflammatory response of infiltrated macrophages. BMC Complement Med Ther 2022;22:17.
DOI: https://doi.org/10.1186/s12906-021-03477-x
Zhong Y, Lee K, Deng Y, Ma Y, Chen Y, Li X, et al. Arctigenin attenuates diabetic kidney disease through the activation of PP2A in podocytes. Nat Commun 2019;10:4523.
DOI: https://doi.org/10.1038/s41467-019-12433-w
Lu R, Zhou J, Liu B, Liang N, He Y, Bai L, et al. Paeoniflorin ameliorates Adriamycin-induced nephrotic syndrome through the PPARγ/ANGPTL4 pathway in vivo and vitro. Biomed Pharmacother 2017;96:137-47.
DOI: https://doi.org/10.1016/j.biopha.2017.09.105
Yang WT, Wang Y, Shi YH, Fu H, Xu Z, Xu QQ, et al. Herbal compatibility of ginseng and rhubarb exerts synergistic neuroprotection in cerebral ischemia/reperfusion injury of rats. Front Physiol 2019;10:1174.
DOI: https://doi.org/10.3389/fphys.2019.01174
Qin Y, Li M, Tian Y, Zhao P, Li K, Li C, et al. [Compatibility characteristics of Bufei Yishen formula III in regulating chronic obstructive pulmonary disease mucus hypersecretion].[Article in Chinese]. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2021;33:1309-14.
Cheng CW, Wu TX, Shang HC, Li YP, Altman DG, Moher D, et al. CONSORT Extension for Chinese herbal medicine formulas 2017: Recommendations, explanation, and elaboration (simplified Chinese version). Ann Intern Med 2017;167:112-21.
DOI: https://doi.org/10.7326/M16-2977
Zhai R, Jian G, Chen T, Xie L, Xue R, Gao C, et al. Astragalus membranaceus and Panax notoginseng, the novel renoprotective compound, synergistically protect against podocyte injury in streptozotocin-induced diabetic rats. J Diabetes Res 2019;2019:1602892.
DOI: https://doi.org/10.1155/2019/1602892
Chan KW, Chow TY, Yu KY, Feng Y, Lao L, Bian Z, et al. Effectiveness of integrative Chinese-Western medicine for chronic kidney disease and diabetes: A retrospective cohort study. Am J Chin Med 2022;50:371-88.
DOI: https://doi.org/10.1142/S0192415X2250015X
Hu HL, Fu CM, Zhao X, Zhang JM, Gao F, He Y, et al. [Comprehensive analysis on "toxicity and effect" of Chinese pharmaceutical preparations].[Article in Chinese]. Zhongguo Zhong Yao Za Zhi 2016;41:3483-9.
Hoxhaj G, Manning BD. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat Rev Cancer 2020;20:74-88.
DOI: https://doi.org/10.1038/s41568-019-0216-7
Su X, Shen Z, Yang Q, Sui F, Pu J, Ma J, et al. Vitamin C kills thyroid cancer cells through ROS-dependent inhibition of MAPK/ERK and PI3K/AKT pathways via distinct mechanisms. Theranostics 2019;9:4461-73.
DOI: https://doi.org/10.7150/thno.35219
Lei L, Zhao J, Liu XQ, Chen J, Qi XM, Xia LL, et al. Wogonin alleviates kidney tubular epithelial injury in diabetic nephropathy by inhibiting PI3K/Akt/NF-κB signaling pathways. Drug Des Devel Ther 2021;15:3131-50.
DOI: https://doi.org/10.2147/DDDT.S310882
Ravindran S PM, Agouni A, Munusamy S. Microparticles as potential mediators of high glucose-induced renal cell injury. Biomolecules 2019;9:348.
DOI: https://doi.org/10.3390/biom9080348
Bozic M, Caus M, Rodrigues-Diez RR, Pedraza N, Ruiz-Ortega M, Garí E, et al. Protective role of renal proximal tubular alpha-synuclein in the pathogenesis of kidney fibrosis. Nat Commun 2020;11:1943.
DOI: https://doi.org/10.1038/s41467-020-15732-9
Huang WJ, Fu Q, Xiao YH, Gong Q, Wu WJ, Shen ZL, et al. 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.
DOI: https://doi.org/10.1155/2018/8421979
Xu ZJ, Shu S, Li ZJ, Liu YM, Zhang RY, Zhang Y. Liuwei Dihuang pill treats diabetic nephropathy in rats by inhibiting of TGF-β/SMADS, MAPK, and NF-kB and upregulating expression of cytoglobin in renal tissues. Medicine (Baltimore) 2017;96:e5879.
DOI: https://doi.org/10.1097/MD.0000000000005879
Hernandez-Quiles M, Broekema MF, Kalkhoven E. PPARgamma in metabolism, immunity, and cancer: Unified and diverse mechanisms of action. Front Endocrinol (Lausanne) 2021;12:624112.
DOI: https://doi.org/10.3389/fendo.2021.624112
Patial V, Katoch S, Chhimwal J, Singh PP, Suresh PS, Padwad Y. Tinospora cordifolia activates PPARγ pathway and mitigates glomerular and tubular cell injury in diabetic kidney disease. Phytomedicine 2021;91:153663.
DOI: https://doi.org/10.1016/j.phymed.2021.153663
Kökény G CL, Hansmann G. PPARγ and TGFβ-Major Regulators of metabolism, inflammation, and fibrosis in the lungs and kidneys. Int J Mol Sci 2021;22:10431.
DOI: https://doi.org/10.3390/ijms221910431
Kawai T, Masaki T, Doi S, Arakawa T, Yokoyama Y, Doi T, et al. PPAR-gamma agonist attenuates renal interstitial fibrosis and inflammation through reduction of TGF-beta. Lab Invest 2009;89:47-58.
DOI: https://doi.org/10.1038/labinvest.2008.104
Wang Z, Liu Q, Dai W, Hua B, Li H, Li W. Pioglitazone downregulates Twist-1 expression in the kidney and protects renal function of Zucker diabetic fatty rats. Biomed Pharmacother 2019;118:109346.
DOI: https://doi.org/10.1016/j.biopha.2019.109346
Ethics Approval
This study was approved by the Ethics Committee of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital and conducted according to the international rules and guidelines.How to Cite
Wang, Z. ., Jian, G., Chen, T. ., Chen, Y. ., Li, J. ., & Wang, N. . (2023). The Qi-Bang-Yi-Shen formula ameliorates renal dysfunction and fibrosis in rats with diabetic kidney disease <em>via</em> regulating PI3K/AKT, ERK and PPARγ signaling pathways. European Journal of Histochemistry, 67(1). https://doi.org/10.4081/ejh.2023.3648
Copyright (c) 2023 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.
Similar Articles
- Federico Angelo Cazzaniga, Edoardo Bistaffa, Chiara Maria Giulia De Luca, Giuseppe Bufano, Antonio Indaco, Giorgio Giaccone, Fabio Moda, Sporadic Creutzfeldt-Jakob disease: Real-Time Quaking Induced Conversion (RT-QuIC) assay represents a major diagnostic advance , European Journal of Histochemistry: Vol. 65 No. s1 (2021): Special Collection on Advances in Neuromorphology in Health and Disease
- C. Severi, R. Sferra, A. Scirocco, A. Vetuschi, N. Pallotta, A. Pronio, R. Caronna, G. Di Rocco, E. Gaudio, E. Corazziari, P. Onori, Contribution of intestinal smooth muscle to Crohn's disease fibrogenesis , European Journal of Histochemistry: Vol. 58 No. 4 (2014)
- J.H. Song, M.Y. Lee, Y.J. Kim, S.R. Park, J. Kim, S.Y. Ryu, J.Y. Jung, Developmental immunolocalization of the Klotho protein in mouse kidney epithelial cells , European Journal of Histochemistry: Vol. 58 No. 1 (2014)
- Liuchang Feng, Zaoqiang Lin, Zeyong Tang, Lin Zhu, Shu Xu, Xi Tan, Xinyuan Wang, Jianling Mai, Qinxiang Tan, Emodin improves renal fibrosis in chronic kidney disease by regulating mitochondrial homeostasis through the mediation of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) , European Journal of Histochemistry: Vol. 68 No. 2 (2024)
- G. Tsirakis, C. A. Pappa, M. Kaparou, V. Katsomitrou, A. Hatzivasili, T. Alegakis, A. Xekalou, E. N. Stathopoulos, M. Alexandrakis, Assessment of proliferating cell nuclear antigen and its relationship with proinflammatory cytokines and parameters of disease activity in multiple myeloma patients , European Journal of Histochemistry: Vol. 55 No. 3 (2011)
- N.P.E. Kadoglou, P. Moustardas, A. Kapelouzou, M. Katsimpoulas, A. Giagini, E. Dede, N. Kostomitsopoulos, P.E. Karayannacos, A. Kostakis, C.D. Liapis, The anti-inflammatory effects of exercise training promote atherosclerotic plaque stabilization in apolipoprotein E knockout mice with diabetic atherosclerosis , European Journal of Histochemistry: Vol. 57 No. 1 (2013)
- Guillermo Laguna-Hernández, Carlos A. Rio-Zamorano, Itzel G. Meneses-Ochoa, Alicia E. Brechú-Franco, Histochemistry and immunolocalisation of glucokinin in antidiabetic plants used in traditional Mexican medicine , European Journal of Histochemistry: Vol. 61 No. 2 (2017)
- J. Hansson, A.E. Ericsson, H. Axelson, M.E. Johansson, Species diversity regarding the presence of proximal tubular progenitor cells of the kidney , European Journal of Histochemistry: Vol. 60 No. 1 (2016)
- Zhijiang Chen, Huili Wang, Bin Hu, Xinxin Chen, Meiyu Zheng, Lili Liang, Juanjuan Lyu, Qiyi Zeng, Transcription factor nuclear factor erythroid 2 p45-related factor 2 (NRF2) ameliorates sepsis-associated acute kidney injury by maintaining mitochondrial homeostasis and improving the mitochondrial function , European Journal of Histochemistry: Vol. 66 No. 3 (2022)
- D. Fanni, N. Iacovidou, A. Locci, C. Gerosa, S. Nemolato, P. Van Eyken, G. Monga, S. Mellou, G. Faa, V. Fanos, MUC1 marks collecting tubules, renal vesicles, comma- and S-shaped bodies in human developing kidney , European Journal of Histochemistry: Vol. 56 No. 4 (2012)
You may also start an advanced similarity search for this article.
