盐皮质激素受体拮抗剂对糖尿病肾病的作用研究进展
Research Progress of Mineralocorticoid Receptor Antagonists on Diabetic Kidney Disease
DOI: 10.12677/ACM.2023.131065, PDF,    科研立项经费支持
作者: 王 璇*, 谢席胜#:川北医学院第二临床学院(南充市中心医院)肾内科,四川 南充;慢性肾脏病基础与临床研究南充市重点实验室,四川 南充
关键词: 糖尿病肾病盐皮质激素受体拮抗剂醛固酮肾心保护Diabetic Kidney Disease Mineralocorticoid Receptor Antagonists Aldosterone Renal Heart Protection
摘要: 糖尿病肾病(diabetic kidney disease, DKD)作为糖尿病(diabetes mellitus, DM)的一个常见且严重并发症,目前已成为全球终末期肾衰竭(ESRD)的主要病因。因此,预防和治疗DKD至关重要。盐皮质激素受体拮抗剂(MRA)通过阻断盐皮质激素受体(MR)过度活化引起的氧化应激、炎症、纤维化作用实现对DKD的肾、心双重获益,成为延缓DKD进展的新选择之一。本文就盐皮质激素及MR的病理生理作用机制以及MRA对DKD作用研究等内容进行综述。
Abstract: Diabetic kidney disease (DKD), a common and serious complication of diabetes mellitus (DM), has become the main cause of end-stage renal disease (ESRD) worldwide. Therefore, prevention and treatment of DKD are crucial. Mineralocorticoid receptor antagonist (MRA) can achieve both renal and cardiac benefits of DKD by blocking the oxidative stress, inflammation and fibrosis caused by the over-activation of mineralocorticoid receptor (MR), becoming one of the new options to delay the progression of DKD. This paper reviews the pathophysiological mechanism of mineralocorticoid and MR as well as the effects of MRA on DKD.
文章引用:王璇, 谢席胜. 盐皮质激素受体拮抗剂对糖尿病肾病的作用研究进展[J]. 临床医学进展, 2023, 13(1): 427-435. https://doi.org/10.12677/ACM.2023.131065

参考文献

[1] Saeedi, P., Petersohn, I., Salpea, P., et al. (2019) Global and Regional Diabetes Prevalence Estimates for 2019 and Pro-jections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th Edition. Diabetes Re-search and Clinical Practice, 157, Article ID: 107843. [Google Scholar] [CrossRef] [PubMed]
[2] Ruiz-Ortega, M., Rodrigues-Diez, R.R., Lavoz, C., et al. (2020) Special Issue “Diabetic Nephropathy: Diagnosis, Prevention and Treatment”. Journal of Clinical Medicine, 9, 813. [Google Scholar] [CrossRef] [PubMed]
[3] 中华医学会肾脏病学分会专家组. 糖尿病肾脏疾病临床诊疗中国指南[J]. 中华肾脏病杂志, 2021, 37(3): 255-304.
[4] Saran, R., et al. (2020) US Renal Data System 2019 Annual Data Report: Epidemiology of Kidney Disease in the United States. American Journal of Kidney Diseases, 75, A6-A7.
[5] Cheng, H.T., Xu, X., Lim, P.S., et al. (2021) Worldwide Epidemiology of Diabetes-Related End-Stage Renal Disease, 2000-2015. Diabetes Care, 44, 89-97. [Google Scholar] [CrossRef] [PubMed]
[6] Wang, F., Yang, C., Long, J., et al. (2019) Executive Summary for the 2015 Annual Data Report of the China Kidney Disease Network (CK-NET). Kidney International, 95, 501-505. [Google Scholar] [CrossRef] [PubMed]
[7] Zuo, C. and Xu, G. (2019) Efficacy and Safety of Mineralocorticoid Receptor Antagonists with ACEI/ARB Treatment for Diabetic Nephrop-athy: A Meta-Analysis. International Journal of Clinical Practice, e13413. [Google Scholar] [CrossRef] [PubMed]
[8] Jaisser, F. and Farman, N. (2016) Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology. Pharmacological Reviews, 68, 49-75. [Google Scholar] [CrossRef] [PubMed]
[9] Guichard, J.L., Clark, D., Calhoun, D.A., et al. (2013) Aldosterone Receptor Antagonists: Current Perspectives and Therapies. Vascular Health and Risk Management, 9, 321-331. [Google Scholar] [CrossRef
[10] Yang, P., Huang, T. and Xu, G. (2016) The Novel Mineralocorticoid Receptor Antagonist Finerenone in Diabetic Kidney Disease: Progress and Challenges. Metabolism, 65, 1342-1349. [Google Scholar] [CrossRef] [PubMed]
[11] Shrestha, A., Che, R.C. and Zhang, A.H. (2019) Role of Al-dosterone in Renal Fibrosis. Advances in Experimental Medicine and Biology, 1165, 325-346. [Google Scholar] [CrossRef] [PubMed]
[12] Young, M.J. and Rickard, A.J. (2015) Mineralocorticoid Re-ceptors in the Heart: Lessons from Cell-Selective Transgenic Animals. Journal of Endocrinology, 224, R1-13. [Google Scholar] [CrossRef
[13] Fraccarollo, D., Berger, S., Galuppo, P., et al. (2011) Deletion of Car-diomyocyte Mineralocorticoid Receptor Ameliorates Adverse Remodeling after Myocardial Infarction. Circulation, 123, 400-408. [Google Scholar] [CrossRef
[14] Alicic, R.Z., Rooney, M.T. and Tuttle, K.R. (2017) Diabetic Kidney Disease: Challenges, Progress, and Possibilities. Clinical Journal of the American Society of Nephrology, 12, 2032-2045. [Google Scholar] [CrossRef
[15] Nishiyama, A. (2019) Pathophysiological Mechanisms of Mineralocorticoid Receptor-Dependent Cardiovascular and Chronic Kidney Disease. Hypertension Research, 42, 293-300. [Google Scholar] [CrossRef] [PubMed]
[16] Mongia, A., Vecker, R. and George, M., et al. (2012) Role of 11betaHSD Type 2 Enzyme Activity in Essential Hypertension and Children with Chronic Kidney Disease (CKD). The Journal of Clinical Endocrinology & Metabolism, 97, 3622-3629. [Google Scholar] [CrossRef] [PubMed]
[17] Gant, C.M., Minovic, I., Binnenmars, H., et al. (2018) Lower Renal Function Is Associated with Derangement of 11-beta Hydroxysteroid Dehydrogenase in Type 2 Diabetes. Journal of the Endocrine Society, 2, 609-620. [Google Scholar] [CrossRef] [PubMed]
[18] Nagase, M. and Fujita, T. (2013) Role of Rac1-Mineralocorticoid-Receptor Signalling in Renal and Cardiac Disease. Nature Reviews Nephrology, 9, 86-98. [Google Scholar] [CrossRef] [PubMed]
[19] Kawarazaki, W. and Fujita, T. (2021) Kidney and Epigenetic Mecha-nisms of Salt-Sensitive Hypertension. Nature Reviews Nephrology, 17, 350-363. [Google Scholar] [CrossRef] [PubMed]
[20] Hall, J.E., Do Carmo, J.M., Da Silva, A.A., et al. (2019) Obesity, Kidney Dysfunction and Hypertension: Mechanistic Links. Nature Reviews Nephrology, 15, 367-385. [Google Scholar] [CrossRef] [PubMed]
[21] Quinkler, M., Zehnder, D., Eardley, K.S., et al. (2005) Increased Expression of Mineralocorticoid Effector Mechanisms in Kidney Biopsies of Patients with Heavy Proteinuria. Circula-tion, 112, 1435-1443. [Google Scholar] [CrossRef
[22] Staessen, J., Lijnen, P., Fagard, R., et al. (1981) Rise in Plasma Concentration of Aldosterone during Long-Term Angiotensin II Suppression. Journal of Endocrinology, 91, 457-465. [Google Scholar] [CrossRef] [PubMed]
[23] Navaneethan, S.D. and Bravo, E.L. (2013) Aldosterone Breakthrough during Angiotensin Receptor Blocker Use: More Questions than Answers? Clinical Journal of the Ameri-can Society of Nephrology, 8, 1637-1639. [Google Scholar] [CrossRef
[24] Barry, M.B., Renner, M.D. and Mark, E. (2001) Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy. The New England Journal of Medicine, 345, 12. [Google Scholar] [CrossRef
[25] Shunan, F., Jiqing Y., Xue D. (2018) Effects of Angioten-sin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on Cardiovascular Events in Patients with Diabe-tes and Overt Nephropathy: A Meta-Analysis of Randomised Controlled Trials. Journal of the Ren-in-Angiotensin-Aldosterone System, 19, 1-9. [Google Scholar] [CrossRef] [PubMed]
[26] Bomback, A.S. and Klemmer, P.J. (2007) The Incidence and Im-plications of Aldosterone Breakthrough. Nature Clinical Practice Nephrology, 3, 486-492. [Google Scholar] [CrossRef] [PubMed]
[27] Parving, H.H., Brenner, B.M., Mcmurray, J.J., et al. (2012) Cardiorenal End Points in a Trial of Aliskiren for Type 2 Diabetes. The New England Journal of Medicine, 367, 2204-2213. [Google Scholar] [CrossRef
[28] Fried, L.F., Emanuele, N., Zhang, J.H., et al. (2013) Combined An-giotensin Inhibition for the Treatment of Diabetic Nephropathy. The New England Journal of Medicine, 369, 1892-1903. [Google Scholar] [CrossRef
[29] Bauersachs, J., Jaisser, F. and Toto, R. (2015) Mineralocorticoid Receptor Activation and Mineralocorticoid Receptor Antagonist Treatment in Cardiac and Renal Diseases. Hypertension, 65, 257-263. [Google Scholar] [CrossRef
[30] Mora-Fernandez, C., Dominguez-Pimentel, V., De Fuentes, M.M., et al. (2014) Diabetic Kidney Disease: From Physiology to Therapeutics. The Journal of Physiology, 592, 3997-4012. [Google Scholar] [CrossRef] [PubMed]
[31] Mehdi, U.F., Adams-Huet, B., Raskin, P., et al. (2009) Addition of Angiotensin Receptor Blockade or Mineralocorticoid Antagonism to Maximal Angioten-sin-Converting Enzyme Inhibition in Diabetic Nephropathy. Journal of the American Society of Nephrology, 20, 2641-2650. [Google Scholar] [CrossRef
[32] Esteghamati, A., Noshad, S., Jarrah, S., et al. (2013) Long-Term Effects of Addition of Mineralocorticoid Receptor Antagonist to Angiotensin II Receptor Blocker in Patients with Diabetic Nephropathy: A Randomized Clinical Trial. Nephrology Dialysis Transplantation, 28, 2823-2833. [Google Scholar] [CrossRef] [PubMed]
[33] Makhlough, A., Kashi, Z., Akha, O., et al. (2014) Effect of Spironolactone on Diabetic Nephropathy Compared to the Combination of Spironolactone and Losartan. Nephro-Urology Monthly, 6, e12148. [Google Scholar] [CrossRef] [PubMed]
[34] Hou, J., Xiong, W., Cao, L., et al. (2015) Spironolactone Add-On for Preventing or Slowing the Progression of Diabetic Nephropathy: A Meta-Analysis. Clinical Therapeutics, 37, 2086-2103e2010. [Google Scholar] [CrossRef] [PubMed]
[35] Tofte, N., Lindhardt, M., Adamova, K., et al. (2020) Early De-tection of Diabetic Kidney Disease by Urinary Proteomics and Subsequent Intervention with Spironolactone to Delay Progression (PRIORITY): A Prospective Observational Study and Embedded Randomised Placebo-Controlled Trial. The Lancet Diabetes & Endocrinology, 8, 301-312. [Google Scholar] [CrossRef
[36] Pitt, B., Zannad, F., Remme, W.J., et al. (1999) The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure. Randomized Aldactone Evaluation Study Investigators. The New England Journal of Medicine, 341, 709-717. [Google Scholar] [CrossRef
[37] Pitt, B., Pfeffer, M.A., Assmann, S.F., et al. (2014) Spiro-nolactone for Heart Failure with Preserved Ejection Fraction. The New England Journal of Medicine, 370, 1383-1392. [Google Scholar] [CrossRef
[38] Funder, J.W. (2019) Aldosterone Research: 65 Years, and Counting. Vitamins and Hormones, 109, 1-15. [Google Scholar] [CrossRef] [PubMed]
[39] Kolkhof, P., Jaisser, F., Kim, S.Y., et al. (2017) Steroidal and Novel Non-Steroidal Mineralocorticoid Receptor Antagonists in Heart Failure and Cardiorenal Diseases: Comparison at Bench and Bedside. Handbook of Experimental Pharmacology, 243, 271-305. [Google Scholar] [CrossRef] [PubMed]
[40] Epstein, M., Buckalew, V. and Martinez, F. (2002) OR-54: Antipro-teinuric Efficacy of Eplerenone, Enalapril, and Eplerenone/Enalapril Combination Therapy in Diabetic Hypertensives with Microalbuminuria. American Journal of Hypertension, 15, 24A. [Google Scholar] [CrossRef
[41] Epstein, M., Williams, G.H., Weinberger, M., et al. (2006) Selective Aldosterone Blockade with Eplerenone Reduces Albuminuria in Patients with Type 2 Diabetes. Clinical Journal of the American Society of Nephrology, 1, 940-951. [Google Scholar] [CrossRef
[42] El Mokadem, M., Abd El Hady, Y. and Aziz, A. (2020) A Prospective Single-Blind Randomized Trial of Ramipril, Eplerenone and Their Combination in Type 2 Diabetic Nephropathy. Cardi-orenal Medicine, 10, 392-401. [Google Scholar] [CrossRef] [PubMed]
[43] Brandt-Jacobsen, N.H., Johansen, M.L., Rasmussen, J., et al. (2021) Ef-fect of High-Dose Mineralocorticoid Receptor Antagonist Eplerenone on Urinary Albumin Excretion in Patients with Type 2 Diabetes and High Cardiovascular Risk: Data from the MIRAD Trial. Diabetes & Metabolism, 47, Article ID: 101190. [Google Scholar] [CrossRef] [PubMed]
[44] Hu, H., Zhao, X., Jin, X., et al. (2022) Efficacy and Safety of Eplerenone Treatment for Patients with Diabetic Nephropathy: A Meta-Analysis. PLOS ONE, 17, e0265642. [Google Scholar] [CrossRef] [PubMed]
[45] Pitt, B.R.W., Zannad, F., et al. (2003) Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial Infarction. The New England Jour-nal of Medicine, 348, 1309-1321. [Google Scholar] [CrossRef
[46] Zannad, F.M.J. and Krum, H. (2011) Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms. The New England Journal of Medicine, 364, 11-21. [Google Scholar] [CrossRef
[47] Amazit, L., Le Billan, F., Kolkhof, P., et al. (2015) Finerenone Im-pedes Aldosterone-Dependent Nuclear Import of the Mineralocorticoid Receptor and Prevents Genomic Recruitment of Steroid Receptor Coactivator-1. Journal of Biological Chemistry, 290, 21876-21889. [Google Scholar] [CrossRef
[48] Agarwal, R., Kolkhof, P., Bakris, G., et al. (2021) Steroidal and Non-Steroidal Mineralocorticoid Receptor Antagonists in Cardiorenal Medicine. European Heart Journal, 42, 152-161. [Google Scholar] [CrossRef] [PubMed]
[49] Pitt, B., Kober, L., Ponikowski, P., et al. (2013) Safety and Tolera-bility of the Novel Non-Steroidal Mineralocorticoid Receptor Antagonist BAY 94-8862 in Patients with Chronic Heart Failure and Mild or Moderate Chronic Kidney Disease: A Randomized, Double-Blind Trial. European Heart Journal, 34, 2453-2463. [Google Scholar] [CrossRef] [PubMed]
[50] Bakris, G.L., Agarwal, R., Chan, J.C., et al. (2015) Effect of Finere-none on Albuminuria in Patients with Diabetic Nephropathy: A Randomized Clinical Trial. JAMA, 314, 884-894. [Google Scholar] [CrossRef] [PubMed]
[51] Bakris, G.L., Agarwal, R., Anker, S.D., et al. (2020) Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. New England Journal of Medicine, 383, 2219-2229. [Google Scholar] [CrossRef
[52] Pitt, B., Anker, S.D., Bohm, M., et al. (2015) Rationale and Design of MinerAlocorticoid Receptor Antagonist Tolerability Study-Heart Failure (ARTS-HF): A Randomized Study of Finerenone vs. Eplerenone in Patients Who Have Worsening Chronic Heart Failure with Diabetes and/or Chronic Kidney Disease. European Journal of Heart Failure, 17, 224-232. [Google Scholar] [CrossRef] [PubMed]
[53] Pitt, B., Filippatos, G., Agarwal, R., et al. (2021) Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes. The New England Journal of Medicine, 385, 2252-2263. [Google Scholar] [CrossRef
[54] Wada, T., Inagaki, M., Yoshinari, T., et al. (2021) Apararenone in Patients with Diabetic Nephropathy: Results of a Randomized, Double-Blind, Placebo-Controlled Phase 2 Dose-Response Study and Open-Label Extension Study. Clinical and Experimental Nephrology, 25, 120-130. [Google Scholar] [CrossRef] [PubMed]
[55] Ito, S., Shikata, K., Nangaku, M., et al. (2019) Efficacy and Safety of Esaxerenone (CS-3150) for the Treatment of Type 2 Diabetes with Microalbuminuria: A Randomized, Dou-ble-Blind, Placebo-Controlled, Phase II Trial. Clinical Journal of the American Society of Nephrology, 14, 1161-1172. [Google Scholar] [CrossRef
[56] Ito, S., Kashihara, N., Shikata, K., et al. (2020) Esaxerenone (CS-3150) in Patients with Type 2 Diabetes and Microalbuminuria (ESAX-DN): Phase 3 Randomized Controlled Clinical Trial. Clinical Journal of the American Society of Nephrology, 15, 1715-1727. [Google Scholar] [CrossRef
[57] Wu, Y., Lin, H., Tao, Y., et al. (2022) Network Meta-Analysis of Mineralocorticoid Receptor Antagonists for Diabetic Kidney Disease. Frontiers in Pharmacology, 13, Article ID: 967317. [Google Scholar] [CrossRef] [PubMed]
[58] Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group (2022) KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney International, 102, S1-S127. [Google Scholar] [CrossRef] [PubMed]