Nephroprotective effect of propionic acid via mitigation of oxidative stress and inflammation in experimental type 2 diabetic rats

Oluwatosin Okunlola; Folasade Omobolanle Ajao; Kehinde Samuel Olaniyi; Noheem Olaoluwa Kalejaiye; Marcus Olaoye Iyedupe

doi:10.5281/zenodo.17148460

Authors

Oluwatosin Okunlola Physiology Department, Faculty of Basic Medical Science, College of Health Science, Ladoke Akintola University of Technology, P.M.B. 4000, Ogbomoso, Oyo State, Nigeria https://orcid.org/0009-0003-5315-8530
Folasade Omobolanle Ajao Physiology Department, Faculty of Basic Medical Science, College of Health Science, Ladoke Akintola University of Technology, P.M.B. 4000, Ogbomoso, Oyo State, Nigeria https://orcid.org/0000-0001-8839-4689
Kehinde Samuel Olaniyi Physiology Department, Faculty of Basic Medical Science, College of Health Science, Ladoke Akintola University of Technology, P.M.B. 4000, Ogbomoso, Oyo State, Nigeria https://orcid.org/0000-0002-8229-9688
Noheem Olaoluwa Kalejaiye Physiology Department, Faculty of Basic Medical Science, College of Health Science, Ladoke Akintola University of Technology, P.M.B. 4000, Ogbomoso, Oyo State, Nigeria https://orcid.org/0009-0007-3949-8220
Marcus Olaoye Iyedupe Physiology Department, Faculty of Basic Medical Science, College of Health Science, Ladoke Akintola University of Technology, P.M.B. 4000, Ogbomoso, Oyo State, Nigeria https://orcid.org/0000-0003-0992-6857

DOI:

https://doi.org/10.5281/zenodo.17148460

Keywords:

Propionic acid, kidney biomarkers, lipid profile, oxidative stress, inflammation

Abstract

Objective: Discovering a novel compound from medicinal plants as alternative medicine to manage diabetes and related complications is a global issue. This study investigated the renoprotective effects of propionic acid in high-fat diet (HFD)/streptozotocin (STZ)-induced rat model.

Materials and methods: Fifty male mature rats (200 ± 20 g) were used. Rats were fed with HFD for 8 weeks. A repeated dose of freshly prepared STZ (30 mg/kgb.wt) was injected intraperitoneally to induce diabetes. The rats were grouped into 5 groups (n=10). Group I: control; Group II: control + 60 mg/kgb.wt propionic acid; Group III: diabetic control; Group IV: diabetic + 60 mg/kgb.wt propionic acid; Group V: diabetic + 200 mg/kgb.wt metformin. The rats were anaesthetized and sacrificed after 21 days of treatment. Serum retrieved from the blood samples and supernatant plasma obtained from kidney homogenates after centrifugation were used for biochemical assay.

Results: Insulin, fasting blood glucose (FBG), glycated hemoglobin (HbA1c), kidney potassium, creatinine, urea, uric acid, triglycerides, total-cholesterol (TC), low-density-lipoprotein (LDL-C), malondialdehyde, tumor-necrosis-factor-α (TNF-α), transformation-growth-factor-beta (TGF-β), interleukin-6 (IL-6),and caspase-3 significantly (p<0.001) increased in diabetic rats. Body weight, high-density-lipoprotein (HDL-C), chloride bicarbonate, sodium, superoxide dismutase (SOD), catalase, reduced glutathione (GSH) and Bcl-2 decreased significantly. Propionic acid administration reduced insulin, FBG, HbA1c, kidney biomarkers, triglycerides, TC, LDL-C, malondialdehyde and inflammatory markers. Body weight, antioxidant activity, HDL-C and Bcl-2 levels were improved.

Conclusion: Propionic acid attenuated kidney oxidative stress and inflammation. Therefore, propionic acid could be used to prevent renal damage and improve renal function in diabetes.

References

Joseph A, Thirupathamma M, Mathews E, Alagu M. Genetics of type 2 diabetes mellitus in Indian and Global Population: A Review. Egypt J Med Hum Genet. 2022;23:135.

International Diabetes Federation. IDF Diabetes Atlas Tenth Edition. (cited 10 September 2022). Available from: https://diabetesatlas.org/

Ojo OA, Ibrahim HS, Rotimi DE, Ogunlakin AD, Ojo AB. Diabetes mellitus: From molecular mechanism to pathophysiology and pharmacology. Med Novel Technol Devices. 2023;19:100247.

DeFronzo RA, Tripathy D. Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care. 2009;32 Suppl 2:S157–63.

Aghaei Zarch SM, Dehghan Tezerjani M, Talebi M, Vahidi Mehrjardi MY. Molecular biomarkers in diabetes mellitus (DM). Med J Islam Repub Iran. 2020;34:28.

Halim M, Halim A. The effects of inflammation, aging and oxidative stress on the pathogenesis of diabetes mellitus (type 2 diabetes). Diabetes Metab Syndr. 2019;13:1165-72.

Asmat U, Abad K, Ismail K. Diabetes mellitus and oxidative stress: A concise review. Saudi Pharm J. 2016;24:547-53.

Dludla PV, Mabhida SE, Ziqubu K, Nkambule BB, Mazibuko-Mbeje SE, Hanser S, et al. Pancreatic β-cell dysfunction in type 2 diabetes: Implications of inflammation and oxidative stress. World J Diabetes. 2023;14(3):130-46.

Berbudi A, Rahmadika N, Tjahjadi AI, Ruslami R. Type 2 Diabetes and its impact on the immune system. Curr Diabetes Rev. 2020;16:442-9.

Pillai A, Fulmali D. A narrative review of new treatment options for diabetic nephropathy. Cureus. 2023;15(1):e33235.

Kostovska I, Trajkovska KT, Topuzovska S, Cekovska S, Labudovic D, Kostovski O, et al. Nephrinuria and podocytopathies. Adv Clin Chem. 2022;108:1-36.

Zhou Z, Luo R, Wan Z, Kuang H, Lyu J. Advances in the role of autoantibodies in diabetic nephropathy: review (Article in Chinese). Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2020;36:175-9.

Warren AM, Knudsen ST, Cooper ME. Diabetic nephropathy: an insight into molecular mechanisms and emerging therapies. Expert Opin Ther Targets. 2019;23:579-91.

Maiti AK. Development of biomarkers and molecular therapy based on inflammatory genes in diabetic nephropathy. Int J Mol Sci. 2021;22:9985.

Li Q, Wang X, Guo A, Zheng W, Bi J, He Y, et al. The curative effect of metformin and linagliptin in newly-diagnosed type 2 diabetes patients with nonalcoholic fatty liver disease. Int J Clin Exp Med. 2021;14(1):391-8.

Okur ME, Ozbek H, Polat DC, Yılmaz S, Arslan R. Hypoglycemic activity of Capparis ovata desf. var. palaestina zoh. methanol extract. Braz J Pharm Sci. 2018;54.

Rahman MM, Dhar PS, Anika SF, Ahmed L, Islam MR, Sultana NA, et al. Exploring the plant-derived bioactive substances as anti-diabetic agent: An extensive review. Biomed Pharmacother. 2022;152:113217.

Siracusa R, Fusco R, Peritore AF, Cordaro M, D’Amico R. The antioxidant and anti-inflammatory properties of Anacardium occidentale L. cashew nuts in a mouse model of colitis. Nutrients. 2020;12:834.

Ajao FO, Akanmu O, Iyedupe MO. Comparative effects of cashew nut, leaf and stem bark (Anacardium occidentale L.) on hyperglycemia and associated abnormalities in streptozotocin-induced diabetic rats. J Drug Deliv Ther. 2022;12(4):47-55.

Dias CCQ, Madruga MS, Pintado MM, et al. Cashew nuts (Anacardium occidentale L.) decrease visceral fat, yet augment glucose in dyslipidemic rats. PLoS One. 2019;14(12):e0225736.

Cordaro M, Siracusa R, Fusco R, D’Amico R, Peritore AF. Cashew (Anacardium occidentale L.) nuts counteract oxidative stress and inflammation in an acute experimental model of carrageenan-induced paw edema. Antioxidants. 2020;9:660.

Ajao FO, Iyedupe MO, Akanmu O, Kalejaiye NO, Adegoke AL. Anti-oxidative, anti-inflammatory and anti-apoptotic efficacy of Anacardium occidentale nuts methanolic extract in pancreas of high-fat diet/streptozotocin-induced diabetic rats. Int J Diabetes Clin Res. 2023;10:177.

Tan Y, Zhang Z, Zheng C, Wintergerst KA, Keller BB, Cai L. Mechanisms of diabetic cardiomyopathy and potential therapeutic strategies: preclinical and clinical evidence. Nat Rev Cardiol. 2020;1-23.

Salahuddin M, Jalalpure SS. Antidiabetic activity of aqueous fruit extract of Cucumis trigonus Roxb. in streptozotocin-induced diabetic rats. J Ethnopharmacol. 2010;127:565–7.

Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18(6):499–502.

Natrus LV, Osadchuk YS, Lisakovska OO, Labudzinskyi DO, Klys YG, Chaikovsky YB. Effect of propionic acid on diabetes-induced impairment of unfolded protein response signaling and astrocyte/microglia crosstalk in rat ventromedial nucleus of the hypothalamus. Neural Plast. 2022;2022:6404964.

Boonphang O, Ontawong A, Pasachan T, Phatsara M, Duangjai A, Amornlerdpison D, et al. Antidiabetic and renoprotective effects of Coffea arabica pulp aqueous extract through preserving organic cation transport system mediated oxidative stress pathway in experimental type 2 diabetic rats. Molecules. 2021;26:1907.

Iheagwam FN, Iheagwam OT, Onuoha MK, Ogunlana OO, Chinedu SN. Terminalia catappa aqueous leaf extract reverses insulin resistance, improves glucose transport and activates PI3K/AKT signalling in high fat/streptozotocin‑induced diabetic rats. Sci Rep. 2022;12:10711.

Galicia-Garcia U, Benito-Vicente A, Jebari S, Larrea-Sebal A, Siddiqi H, Uribe KB, et al. Pathophysiology of type 2 diabetes mellitus. Int J Mol Sci. 2020;21(17):6275.

Omoboyowa DA, Afolabi FO, Aribigbola TC. Pharmacological potential of methanol extract of Anacardium occidentale stem bark on alloxan-induced diabetic rats. Biomed Res Ther. 2018;5(7):2440-54.

Adoga JO, Channa ML, Nadar A. Kolaviron attenuates cardiovascular injury in fructose-streptozotocin induced type-2 diabetic male rats by reducing oxidative stress, inflammation, and improving cardiovascular risk markers. Biomed Pharmacother. 2021;144:112323.

Ahmed AA, Alsalmi W. Disturbance of electrolytes (Na, K and Cl) homeostasis among patients with type II diabetes mellitus. Libyan J Med Res. 2022;16(2):153-60.

Lagat JK, Ng'wena AGM, Mwaniki DM. Effects of Achyranthes aspera, Bidens pilosa and Ajuga remota leaf extracts on serum glucose and electrolyte levels in alloxan treated male goats. Afr J Health Sci. 2021;34(4):537-49.

Ojiako OA, Chikezie PC. Blood Na+/K+ and Cl- levels of hyperglycemic rats administered with traditional herbal formulations. Pharmacogn Commun. 2015;5(2):140-4.

Obafemi TO. Gallic and hesperidin ameliorate electrolyte imbalances in AlCl3-induced nephrotoxicity in Wistar rats. Biochem Res Int. 2022;2022:1-10.

Olorunnisola OS, Adetutu A, Popoola RB, Owoade AO, Adegbola P, Adesina BT. Nephroprotective effect of ethanolic leaf extract of Thaumatococcus danielli (Benth.) in streptozotocin induced diabetic rats. Funct Foods Health Dis. 2017;7(12):923-35.

He J, Wan Y, Fan X, Yu H, Qin Y, Su J, et al. Associations between kidney function with all-cause and cause-specific mortality in type 2 diabetes mellitus patients: a prospective cohort study in China. J Health Popul Nutr. 2025;44(1):77.

Laville SM, Couturier A, Lambert O, Metzger M, Mansencal N, et al. Urea levels and cardiovascular disease in patients with chronic kidney disease. Nephrol Dial Transplant. 2022;38(1):184-92.

Tang X, Xu L, Meng RG, Du YQ, Liu SJ, et al. Association between serum uric acid and the early marker of kidney function decline among Chinese middle-aged and older population: evidence from the China health and retirement longitudinal study. Biomed Environ Sci. 2023;36(3):231-40.

Ife AV, Abah MA, Moranyo AE. Effect of Cucumis callosus fruit extract on the liver function of DMBA-induced mammary cancer in female albino Wistar rats. Int J Complement Altern Med. 2024;17(6):255-61.

Soji-Omoniwa O, Falegan MP, Omoniwa BP, Olundegun WM, Jugu TY. Effect of co-administration of metformin and aqueous leaf extract of Bryophyllum pinnatum on kidney function indices in diabetic rats. Sci World J. 2024;19(4).

Almatroodi SA, Alnuqaydan AM, Babiker AY, Almogbel MA, Khan AA, Rahmani AH. 6-Gingerol, a bioactive compound of ginger attenuates renal damage in streptozotocin-induced diabetic rats by regulating the oxidative stress and inflammation. Pharmaceutics. 2021;13:317.

Beverly JK, Budoff MJ. Atherosclerosis: Pathophysiology of insulin resistance, hyperglycemia, hyperlipidemia, and inflammation. J Diabetes. 2020;12(2):102-4.

Adelakuna SA, Akomaye AJ, Omotoso OD, Arowosegbe OA. Anti-hepatopathy and anti-nephropathy activities of Taraxacum officinale in a rat model of streptozotocin diabetes-induced hepatorenal toxicity and dyslipidemia via attenuation of oxidative stress, inflammation, apoptosis, electrolyte imbalances, and mitochondrial dysfunction. Aspects Mol Med. 2024;3:100034.

Abdelazeim SA, Shehata NI, Aly HF, Shams SGE. Amelioration of oxidative stress‐mediated apoptosis in copper oxide nanoparticles‐induced liver injury in rats by potent antioxidants. Sci Rep. 2020;10(1):1-14.

Madić V, Petrović A, Jušković M. Polyherbal mixture ameliorates hyperglycemia, hyperlipidemia and histopathological changes of pancreas, kidney and liver in a rat model of type 1 diabetes. J Ethnopharmacol. 2021;265:113210.

Omiyale BO, Ekundayo BE, Mathenjwa-Goqo MS, Ajiboye BO, Oyinloye BE. Protective effect of phenolic-rich extract of Annona muricata Linn leaf on renal oxidative stress and inflammation in streptozotocin-induced diabetes in diabetic rats. Sci Afr. 2025;27:02515.

Murtaza S, Khan JA, Aslam B, et al. Pomegranate peel extract and quercetin possess antioxidant and hepatoprotective activity against concanavalin A-induced liver injury in mice. Pak Vet J. 2021;41:197-202.

Petsouki E, Cabrera SNS, Heiss EH. AMPK and NRF2: Interactive players in the same team for cellular homeostasis? Free Radic Biol Med. 2022;190:75-93.

Naidoo K, Khathi A. Investigating the effects of gossypetin on liver health in diet-induced pre-diabetic male Sprague Dawley rats. Molecules. 2025;30:1834.

Amorim RG, Guedes GDS, Vasconcelos SMDL, Santos JCDF. Kidney disease in diabetes mellitus: cross-linking between hyperglycemia, redox imbalance and inflammation. Arq Bras Cardiol. 2019;112:577-87.

Chen TL, Xu EL, Lu HJ, Xu H, Wang SF, et al. The influence of diabetes-enhanced inflammation on cell apoptosis and periodontitis. Adv Biosci Biotechnol. 2021;3:712-9.

Ahmad MF, Naseem N, Rahman I, Imam N, Younus H, Pandey SK, et al. Naringin attenuates the diabetic neuropathy in STZ-induced type 2 diabetic Wistar rats. Life. 2022;12:2111.

Dare A, Channa ML, Nada A. L-Ergothioneine and its combination with metformin attenuates renal dysfunction in type-2 diabetic rat model by activating Nrf2 antioxidant pathway. Biomed Pharmacother. 2021;141:111921.

Yang F, Zhang Z, Zhang L. Bisacurone attenuates diabetic nephropathy by ameliorating oxidative stress, inflammation and apoptosis in rats. Hum Exp Toxicol. 2022;41:1-14.

Wang G, Qu FZ, Li L, Lv JC, Sun B. Necroptosis: a potential, promising target and switch in acute pancreatitis. Apoptosis. 2021;21:121-9.