Peroxisome proliferator-activated receptors in metabolic and renal health: a comprehensive review
DOI:
https://doi.org/10.18203/2320-6012.ijrms20252817Keywords:
Chronic kidney disease, Diabetic nephropathy, Glucose metabolism, Lipid metabolism, PPAR agonists, Peroxisome proliferator-activated receptorsAbstract
Peroxisome Proliferator-Activated Receptors (PPARs), including α, β/δ and γ isoforms, play crucial roles in regulating metabolic and renal health. This study explores their involvement in lipid metabolism, inflammation, chronic kidney disease (CKD) and diabetic nephropathy, emphasizing the therapeutic potential of both synthetic and natural PPAR agonists. A comprehensive literature review was conducted using PubMed, Scopus and Google Scholar, with search terms such as "Peroxisome Proliferator-Activated Receptors," "PPAR agonists," "lipid metabolism," "chronic kidney disease," and "diabetic nephropathy." Boolean operators and MeSH terms were applied and studies from 2000 to 2024 were included. Eligibility criteria focused on experimental, clinical and review articles detailing PPAR mechanisms, physiological roles and therapeutic applications. Findings indicate that PPARs are critical in lipid and glucose metabolism, oxidative stress reduction and fibrosis mitigation. Synthetic ligands such as thiazolidinediones and fibrates demonstrate therapeutic efficacy in CKD and metabolic syndrome, though challenges such as side effects and variability persist. While PPAR-targeted treatments offer promise in metabolic and renal disorders, their clinical application requires further refinement through selective modulators, combination therapies and biomarker-guided strategies.
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Michalik L, Auwerx J, Berger JP, Chatterjee VK, Glass CK, Gonzalez FJ, et al. International Union of Pharmacology. LXI. Peroxisome Proliferator-Activated Receptors. Pharmacol Rev. 2006;58(4):726–41. DOI: https://doi.org/10.1124/pr.58.4.5
Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med. 2002;53(1):409–35. DOI: https://doi.org/10.1146/annurev.med.53.082901.104018
Neschen S, Morino K, Dong J, Wang-Fischer Y, Cline GW, Romanelli AJ, et al. N-3 Fatty Acids Preserve Insulin Sensitivity In Vivo in a Peroxisome Proliferator–Activated Receptor-α–Dependent Manner. Diabetes. 2007;56(4):1034–41. DOI: https://doi.org/10.2337/db06-1206
Willson TM, Brown PJ, Sternbach DD, Henke BR. The PPARs: from orphan receptors to drug discovery. J Med Chem. 2000;43(4):527–50. DOI: https://doi.org/10.1021/jm990554g
Medina-Gomez G, Gray SL, Yetukuri L, Shimomura K, Virtue S, Campbell M, et al. PPAR gamma 2 prevents lipotoxicity by controlling adipose tissue expandability and peripheral lipid metabolism. Barsh GS, editor. PLoS Genet. 2007;3(4):64. DOI: https://doi.org/10.1371/journal.pgen.0030064
Kliewer SA, Sundseth SS, Jones SA, Brown PJ, Wisely GB, Koble CS, et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ. Proceedings of the National Acad Sci. 1997;94(9):4318–23. DOI: https://doi.org/10.1073/pnas.94.9.4318
Tyagi S, Gupta P, Saini A, Kaushal C, Sharma S. The peroxisome proliferator-activated receptor: A family of nuclear receptors role in various diseases. J Adv Pharm Technol Res. 2011;2(4):236. DOI: https://doi.org/10.4103/2231-4040.90879
Zhang L, Liu J, Zhou F, Wang W, Chen N. PGC-1α ameliorates kidney fibrosis in mice with diabetic kidney disease through an antioxidative mechanism. Mol Med Rep. 2018;17(3):4490-8. DOI: https://doi.org/10.3892/mmr.2018.8433
Artunc F, Schleicher E, Weigert C, Fritsche A, Stefan N, Häring HU. The impact of insulin resistance on the kidney and vasculature. Nat Rev Nephrol. 2016;12(12):721–37. DOI: https://doi.org/10.1038/nrneph.2016.145
Desvergne B, Wahli W. Peroxisome Proliferator-Activated Receptors: Nuclear Control of Metabolism. Endocr Rev. 1999;20(5):649–88. DOI: https://doi.org/10.1210/edrv.20.5.0380
Libby AE, Jones B, Lopez-Santiago I, Rowland E, Levi M. Nuclear receptors in the kidney during health and disease. Mol Aspects Med. 2021;78:100935. DOI: https://doi.org/10.1016/j.mam.2020.100935
Kostadinova R, Wahli W, Michalik L. PPARs in Diseases: Control Mechanisms of Inflammation. Curr Med Chem. 2005;12(25):2995–3009. DOI: https://doi.org/10.2174/092986705774462905
Schwimmer JB, Behling C, Newbury R, Deutsch R, Nievergelt C, Schork NJ, et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology. 2005;42(3):641–9. DOI: https://doi.org/10.1002/hep.20842
Stephen RL, Gustafsson MCU, Jarvis M, Tatoud R, Marshall BR, Knight D, et al. Activation of Peroxisome Proliferator-Activated Receptor δ stimulates the proliferation of human breast and prostate cancer cell lines. Cancer Res. 2004;64(9):3162–70. DOI: https://doi.org/10.1158/0008-5472.CAN-03-2760
Antza C, Grassi G, Weber T, Persu A, Jordan J, Nilsson PM, et al. Assessment and management of patients with obesity and hypertension in European society of hypertension excellence centres. a survey from the esh working group on diabetes and metabolic risk factors. Blood Press. 2024;33(1):2317256. DOI: https://doi.org/10.1080/08037051.2024.2317256
Cervantes J, Koska J, Kramer F, Akilesh S, Alpers CE, Mullick AE, et al. Elevated apolipoprotein C3 augments diabetic kidney disease and associated atherosclerosis in type 2 diabetes. JCI Insight. 2024;9(12):177268. DOI: https://doi.org/10.1172/jci.insight.177268
Bakris G, Viberti G, Weston WM, Heise M, Porter LE, Freed MI. Rosiglitazone reduces urinary albumin excretion in type II diabetes. J Hum Hypertens. 2003;17(1):7–12. DOI: https://doi.org/10.1038/sj.jhh.1001444
Yang J, Liu Z. Mechanistic Pathogenesis of Endothelial Dysfunction in Diabetic Nephropathy and Retinopathy. Front Endocrinol (Lausanne). 2022;13:816400. DOI: https://doi.org/10.3389/fendo.2022.816400
Tuttle KR, Agarwal R, Alpers CE, Bakris GL, Brosius FC, Kolkhof P, et al. Molecular mechanisms and therapeutic targets for diabetic kidney disease. Kidney Int. 2022;102(2):248–60. DOI: https://doi.org/10.1016/j.kint.2022.05.012
Sharma V, Patial V. Peroxisome proliferator-activated receptor gamma and its natural agonists in the treatment of kidney diseases. Front Pharmacol. 2022;13:991059. DOI: https://doi.org/10.3389/fphar.2022.991059
Sun X, Liu Y, Li C, Wang X, Zhu R, Liu C, et al. Recent Advances of Curcumin in the Prevention and Treatment of Renal Fibrosis. Biomed Res Int. 2017;2017:1–9. DOI: https://doi.org/10.1155/2017/2418671
Botta M, Audano M, Sahebkar A, Sirtori C, Mitro N, Ruscica M. PPAR Agonists and Metabolic Syndrome: An Established Role? Int J Mol Sci. 2018;19(4):1197. DOI: https://doi.org/10.3390/ijms19041197
Boulanger H, Mansouri R, Gautier JF, Glotz D. Are peroxisome proliferator-activated receptors new therapeutic targets in diabetic and non-diabetic nephropathies. Nephrol Dialysis Transplant. 2006;21(10):2696–702. DOI: https://doi.org/10.1093/ndt/gfl448
Mackenzie LS, Lione L. Harnessing the benefits of PPARβ/δ agonists. Life Sci. 2013;93(26):963–7. DOI: https://doi.org/10.1016/j.lfs.2013.10.022
Horita S, Nakamura M, Satoh N, Suzuki M, Seki G. Thiazolidinediones and Edema: Recent Advances in the Pathogenesis of Thiazolidinediones-Induced Renal Sodium Retention. PPAR Res [Internet]. 2015;2015:1–7. Available from: http://www.hindawi.com/journals/ppar/2015/646423/
Chi T, Wang M, Wang X, Yang K, Xie F, Liao Z, et al. PPAR-γ Modulators as Current and Potential Cancer Treatments. Front Oncol. 2021;11:737776. DOI: https://doi.org/10.3389/fonc.2021.737776
Musso G, Cassader M, Cohney S, De Michieli F, Pinach S, Saba F, et al. Fatty liver and chronic kidney disease: novel mechanistic insights and therapeutic opportunities. Diabetes Care. 2016;39(10):1830–45.
Yokote K, Yamashita S, Arai H, Araki E, Suganami H, Ishibashi S. Long-term efficacy and safety of pemafibrate, a novel selective peroxisome Proliferator-Activated Receptor-α Modulator (SPPARMα), in Dyslipidemic Patients with Renal Impairment. Int J Mol Sci. 2019;20(3):706. DOI: https://doi.org/10.3390/ijms20030706
Rubenstrunk A, Hanf R, Hum D, Fruchart J, Staels B. Safety issues and prospects for future generations of PPAR modulators. Mol Cell Biol Lipids. 2007;1771(8):1065–81. DOI: https://doi.org/10.1016/j.bbalip.2007.02.003
Stadler K, Ilatovskaya D V. Renal Epithelial Mitochondria: Implications for Hypertensive Kidney Disease. In: Prakash YS, editor. Comprehensive Physiology. 1st ed. Wiley; 2023: 5225–42. DOI: https://doi.org/10.1002/j.2040-4603.2024.tb00287.x
Sun Y, Liu S, Chen S, Chen J. The Effect of Corticosteroid Injection Into Rotator Interval for Early Frozen Shoulder: A Randomized Controlled Trial. Am J Sports Med. 2018;46(3):663–70. DOI: https://doi.org/10.1177/0363546517744171
Tanaka A, Nakamura T, Sato E, Chihara A, Node K. Effect of pemafibrate, a novel selective peroxisome proliferator-activated receptor-alpha modulator (SPPARMα), on urinary protein excretion in IgA nephropathy with hypertriglyceridemia. CEN Case Rep. 2020;9(2):141–6. DOI: https://doi.org/10.1007/s13730-020-00444-2
Musso G, Cassader M, Cohney S, De Michieli F, Pinach S, Saba F, et al. Fatty liver and chronic kidney disease: novel mechanistic insights and therapeutic opportunities. Diabetes Care. 2016;39(10):1830–45. DOI: https://doi.org/10.2337/dc15-1182
Jao TM, Nangaku M, Wu CH, Sugahara M, Saito H, Maekawa H, et al. ATF6α downregulation of PPARα promotes lipotoxicity-induced tubulointerstitial fibrosis. Kidney Int. 2019;95(3):577–89. DOI: https://doi.org/10.1016/j.kint.2018.09.023
Horita S, Nakamura M, Satoh N, Suzuki M, Seki G. Thiazolidinediones and edema: recent advances in the pathogenesis of thiazolidinediones-induced renal sodium retention. PPAR Res. 2015;2015:1–7. DOI: https://doi.org/10.1155/2015/646423
Komatsu T, Miura T, Joko K, Sunohara D, Mochidome T, Kasai T, et al. Real-world Profile of a Selective Peroxisome Proliferator-activated Receptor α Modulator (SPPARMα) in Japanese Patients with Renal Impairment and Dyslipidemia. Internal Med. 2021;60(17):2741–8. DOI: https://doi.org/10.2169/internalmedicine.6871-20
Ruilope L, Hanefeld M, Lincoff AM, Viberti G, Meyer-Reigner S, Mudie N, et al. Effects of the dual peroxisome proliferator-activated receptor-α/γ agonist aleglitazar on renal function in patients with stage 3 chronic kidney disease and type 2 diabetes: a Phase IIb, randomized study. BMC Nephrol. 2014;15(1):180. DOI: https://doi.org/10.1186/1471-2369-15-180
Barish GD. PPAR : a dagger in the heart of the metabolic syndrome. J Clin Invest. 2006;116(3):590–7. DOI: https://doi.org/10.1172/JCI27955
Hirschfield GM, Bowlus CL, Mayo MJ, Kremer AE, Vierling JM, Kowdley KV, et al. A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis. England J Med. 2024;390(9):783–94. DOI: https://doi.org/10.1056/NEJMoa2312100
Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, et al. Elafibranor, an agonist of the peroxisome proliferator−activated receptor−α and −δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150(5):1147-59. DOI: https://doi.org/10.1053/j.gastro.2016.01.038
Ke Q, Xiao Y, Liu D, Shi C, Shen R, Qin S, et al. PPARα/δ dual agonist H11 alleviates diabetic kidney injury by improving the metabolic disorders of tubular epithelial cells. Biochem Pharmacol. 2024;222:116076. DOI: https://doi.org/10.1016/j.bcp.2024.116076
Omachi K, O’Carroll C, Miner JH. PPARδ Agonism Ameliorates Renal Fibrosis in an Alport Syndrome Mouse Model. Kidney360. 2023;4(3):341–8. DOI: https://doi.org/10.34067/KID.0006662022
Narkar VA, Downes M, Yu RT, Embler E, Wang YX, Banayo E, et al. AMPK and PPARδ agonists are exercise mimetics. Cell. 2008;134(3):405–15. DOI: https://doi.org/10.1016/j.cell.2008.06.051
Bhurruth-Alcor Y, Røst T, Jorgensen MR, Kontogiorgis C, Skorve J, Cooper RG, et al. Synthesis of novel PPARα/γ dual agonists as potential drugs for the treatment of the metabolic syndrome and diabetes type II designed using a new de novo design program PROTOBUILD. Org Biomol Chem. 2011;9(4):1169–88. DOI: https://doi.org/10.1039/C0OB00146E
Paw M, Wnuk D, Madeja Z, Michalik M. PPARδ Agonist GW501516 Suppresses the TGF-β-Induced Profibrotic Response of Human Bronchial Fibroblasts from Asthmatic Patients. Int J Mol Sci. 2023;24(9):7721. DOI: https://doi.org/10.3390/ijms24097721
Gao J, Gu Z. The role of peroxisome proliferator-activated receptors in kidney diseases. Front Pharmacol. 2022;13:832732. DOI: https://doi.org/10.3389/fphar.2022.832732
Itoi E, Berglund LJ, Grabowski JJ, Naggar L, Morrey BF, An KN. Superior-inferior stability of the shoulder: role of the coracohumeral ligament and the rotator interval capsule. 2019;73(6):508–15. DOI: https://doi.org/10.4065/73.6.508
Kintz P, Gheddar L, Paradis C, Chinellato M, Ameline A, Raul JS, et al. Peroxisome proliferator-activated receptor delta agonist (PPAR- δ) and selective androgen receptor modulator (SARM) abuse: clinical, analytical and biological Data in a Case Involving a Poisonous Combination of GW1516 (Cardarine) and MK2866 (Ostarine). Toxics. 2021;9(10):67. DOI: https://doi.org/10.3390/toxics9100251
Lu W, Huang J, Flores J, Li P, Wang W, Liu S, et al. GW0742 reduces mast cells degranulation and attenuates neurological impairments via PPARβ/δ/CD300a/SHP1 pathway after GMH in neonatal rats. Exp Neurol. 2024;372:114615. DOI: https://doi.org/10.1016/j.expneurol.2023.114615
Youssef J, Badr M. Peroxisome proliferator-activated receptors: features, functions, and future. Nuclear Recep Res. 2015;2(1):1-30. DOI: https://doi.org/10.11131/2015/101188
Davidson MH, Armani A, McKenney JM, Jacobson TA. Safety Considerations with Fibrate Therapy. Am J Cardiol. 2007;99(6):3–18. DOI: https://doi.org/10.1016/j.amjcard.2006.11.016
Fruchart JC. Selective peroxisome proliferator-activated receptor α modulators (SPPARMα): the next generation of peroxisome proliferator-activated receptor α-agonists. Cardiovasc Diabetol. 2013;12:82. DOI: https://doi.org/10.1186/1475-2840-12-82
Kim YK, Hwang JG, Park MK. No Relevant Pharmacokinetic Drug–Drug Interaction Between the Sodium-Glucose Co-Transporter-2 Inhibitor Empagliflozin and Lobeglitazone, a Peroxisome Proliferator-Activated Receptor-γ Agonist, in Healthy Subjects. Drug Des Devel Ther. 2021;15:1725–34. DOI: https://doi.org/10.2147/DDDT.S302215
Tenenbaum A, Fisman EZ. Balanced pan-PPAR activator bezafibrate in combination with statin: comprehensive lipids control and diabetes prevention. Cardiovasc Diabetol. 2012;11:140. DOI: https://doi.org/10.1186/1475-2840-11-140
Meyer M, Foulquier S, Dupuis F, Flament S, Grimaud L, Henrion D, et al. Synthesis and evaluation of new designed multiple ligands directed towards both peroxisome proliferator-activated receptor-γ and angiotensin II type 1 receptor. Eur J Med Chem. 2018;158:334–52. DOI: https://doi.org/10.1016/j.ejmech.2018.08.082
Wang L, Waltenberger B, Pferschy-Wenzig EM, Blunder M, Liu X, Malainer C, et al. Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review. Biochem Pharmacol. 2014;92(1):73–89. DOI: https://doi.org/10.1016/j.bcp.2014.07.018
Cataldi S, Costa V, Ciccodicola A, Aprile M. PPARγ and Diabetes: Beyond the Genome and Towards Personalized Medicine. Curr Diab Rep. 2021;21(6):18. DOI: https://doi.org/10.1007/s11892-021-01385-5
Vuppalanchi R, Caldwell SH, Pyrsopoulos N, deLemos AS, Rossi S, Levy C, et al. Proof-of-concept study to evaluate the safety and efficacy of saroglitazar in patients with primary biliary cholangitis. J Hepatol. 2022;76(1):75–85. DOI: https://doi.org/10.1016/j.jhep.2021.08.025
Gawrieh S, Noureddin M, Loo N, Mohseni R, Awasty V, Cusi K, et al. Saroglitazar, a PPAR-α/γ Agonist, for Treatment of NAFLD: A Randomized Controlled Double-Blind Phase 2 Trial. Hepatology. 2021;74(4):1809–24. DOI: https://doi.org/10.1002/hep.31843
Mottl AK, Buse JB, Ismail-Beigi F, Sigal RJ, Pedley CF, Papademetriou V, et al. Long-Term Effects of Intensive Glycemic and Blood Pressure Control and Fenofibrate Use on Kidney Outcomes. Clinical J American Soc Nephrol. 2018;13(11):1693–702. DOI: https://doi.org/10.2215/CJN.06200518
Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus. Ann Intern Med. 2016;165(5):305. DOI: https://doi.org/10.7326/M15-1774
Satirapoj B, Watanakijthavonkul K, Supasyndh O. Safety and efficacy of low dose pioglitazone compared with standard dose pioglitazone in type 2 diabetes with chronic kidney disease: A randomized controlled trial. PLoS One. 2018;13(10):206722. DOI: https://doi.org/10.1371/journal.pone.0206722
Abushamat LA, Schauer IE, Low Wang CC, Mitchell S, Herlache L, Bridenstine M, et al. Rosiglitazone improves insulin resistance but does not improve exercise capacity in individuals with impaired glucose tolerance: A randomized clinical study. J Invest Med. 2024;72(3):294–304. DOI: https://doi.org/10.1177/10815589231225183
Li X, Yu J, Wu M, Li Q, Liu J, Zhang H, et al. Pharmacokinetics and safety of chiglitazar, a peroxisome proliferator‐activated receptor pan‐agonist, in patients < 65 and ≥ 65 years with type 2 diabetes. Clin Pharmacol Drug Dev. 2021;10(7):789–96. DOI: https://doi.org/10.1002/cpdd.893
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