Sains Malaysiana 54(3)(2025): 815-826

http://doi.org/10.17576/jsm-2025-5403-16

Effects of Low-Protein Diet on Renal Oxidative Stress, Biochemistry and Histology in Weaned Rats

(Kesan Diet Rendah Protein terhadap Tekanan Oksidatif Buah Pinggang, Biokimia dan Histologi pada Tikus Cerai Susu)

YEE XIN LEE¹, SEE MENG LIM^2,*, XIN QIAN NG², PEI TENG LUM², ELVY SUHANA MOHD RAMLI³, KOK-YONG CHIN⁴ & SITI BALKIS BUDIN¹

¹Centre for Diagnostic, Therapeutic and Investigative Studies (CODTIS), Faculty of Health Sciences, Universiti Kebangsaan Malaysia, 50300 Kuala Lumpur, Malaysia

²Centre for Community Health Studies (ReaCH), Faculty of Health Sciences, Universiti Kebangsaan Malaysia, 50300 Kuala Lumpur, Malaysia

³Department of Anatomy, Faculty of Medicine, Universiti Kebangsaan Malaysia, 56000 Cheras, Kuala Lumpur, Malaysia

⁴Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, 56000 Cheras, Kuala Lumpur, Malaysia

Diserahkan: 2 September 2024/Diterima: 28 November 2024

Abstract

A low-protein diet (LPD) leads to low plasma protein and insufficient building blocks for normal kidney development, especially in children. This study aimed to determine the effects of short-term LPD on renal oxidative stress, biochemical profile and histologic changes in weaned rats. Three-week-old male and female Sprague Dawley rats were divided into the LPD group and the normal protein diet (NPD) group for 3 weeks. Renal oxidative stress, biochemical profile and histology were examined. Both male and female rats had significantly (p<0.05) lower body weight, smaller kidneys and higher advanced oxidation protein product concentrations after a 3-week LPD. Only LPD-fed females had lower malondialdehyde concentrations and superoxide dismutase activity but higher reduced glutathione concentrations compared to NPD-fed females. Histologic examination showed abnormal histologic features in the proximal and distal tubules, fibrosis in the cuboidal cells, reduced lumen diameter, smaller glomerular tuft area and glomerular tuft volume in LPD-fed male and female groups. In conclusion, short-term protein malnutrition leads to renal injury in male and female weaned rats. The different responses of male and female rats to protein malnutrition suggest sexual dimorphism and hormonal factors in kidney development, with females showing a higher susceptibility to oxidative damage.

Keyword: Kidney; low-protein diet; oxidative stress

Abstrak

Diet rendah protein (LPD) menyebabkan protein plasma yang rendah dan blok binaan yang tidak mencukupi untuk perkembangan ginjal yang normal, terutamanya pada kanak-kanak. Kajian ini bertujuan untuk menentukan kesan jangka pendek LPD terhadap tekanan oksidatif ginjal, profil biokimia dan perubahan histologi ginjal dalam tikus cerai susu. Tikus Sprague Dawley jantan dan betina berusia tiga minggu dibahagikan kepada kumpulan LPD dan kumpulan diet protein biasa (NPD) selama 3 minggu. Tekanan oksidatif ginjal, profil biokimia dan histologi ginjal telah diperiksa. Tikus jantan dan betina mempunyai berat badan yang lebih rendah (p<0.05), ginjal yang lebih kecil dan kepekatan pengoksidaan produk protein lanjutan yang lebih tinggi 3 minggu selepas LPD. Hanya tikus betina yang diberi LPD mempunyai kepekatan malondialdehid dan aktiviti superoksida dismutase yang lebih rendah dan kepekatan glutation terturun yang lebih tinggi berbanding tikus betina yang diberi NPD. Pemeriksaan histologi mendedahkan ciri histologi yang tidak normal dalam tubul proksimal dan distal, fibrosis dalam sel kuboid, diameter lumen yang berkurangan dan kawasan tuf glomerulus dan isi padu tuf glomerulus yang lebih kecil pada kumpulan jantan dan betina yang diberi LPD. Kesimpulannya, malpemakanan protein jangka pendek menyebabkan kecederaan ginjal pada tikus jantan dan betina yang telah bercerai susu. Tindak balas yang berbeza antara tikus jantan dan tikus betina terhadap kekurangan zat protein menunjukkan dimorfisme seks dan faktor hormon dalam perkembangan ginjal, dengan betina menunjukkan kerentanan yang lebih tinggi kepada kerosakan oksidatif.

Kata kunci: Ginjal; pemakanan rendah protein; tekanan oksidatif

RUJUKAN

Adi, G.S., Pratiwi, E. & Amanda, S.P. 2021. Protein Consumption Program (PCP) dalam pencegahan stunting pada anak di masa pandemi corona virus disease 19. Health Sciences and Pharmacy Journal 5(3): 69-73.

Beckerman-Hsu, J.P., Chatterjee, P., Kim, R., Sharma, S. & Subramanian, S. 2020. A typology of dietary and anthropometric measures of nutritional need among children across districts and parliamentary constituencies in India, 2016. Journal of Global Health 10(2): 1-10.

Beyer, W.F. & Fridovich, I. 1987. Assaying for superoxide dismutase activity: Some large consequences of minor changes in conditions. Analytical Biochemistry 161(2): 559-566.

Cao, W., Hou, F.F. & Nie, J. 2014. AOPPs and the progression of kidney disease. Kidney International Supplements 4(1): 102-106.

Cao, W., Xu, J., Zhou, Z.M., Wang, G.B., Hou, F.F. & Nie, J. 2013. Advanced oxidation protein products activate intrarenal renin–angiotensin system via a CD36-mediated, redox-dependent pathway. Antioxidants Redox Signalling 18(1): 19-35.

D'Agati, V.D., Kaskel, F.J. & Falk, R.J. 2011. Focal segmental glomerulosclerosis. The New England Journal of Medicine 365(25): 2398-2411.

D’Marco, L., Puchades, M.J., Escudero-Saiz, V., Giménez-Civera, E., Terradez, L., Moscardó, A., Carbonell-Asins, J.A., Pérez-Bernat, E., Torregrosa, I. & Moncho, F. 2022. Renal histologic findings in necropsies of type 2 diabetes mellitus patients. Journal of Diabetes Research 2022: 3893853.

Dalvi, P.S., Yang, S., Swain, N., Kim, J., Saha, S., Bourdon, C., Zhang, L., Chami, R. & Bandsma, R.H. 2018. Long-term metabolic effects of malnutrition: Liver steatosis and insulin resistance following early-life protein restriction. PLoS ONE 13(7): e0199916.

Ece, A., Gözü, A., Bükte, Y., Tutanç, M. & Kocamaz, H. 2007. The effect of malnutrition on kidney size in children. Pediatric Nephrology 22: 857-863.

Ellman, G.L. 1959. Tissue sulfhydryl groups. Archives of Biochemistry and Biophysics 82(1): 70-77.

Harris, A.N., Castro, R.A., Lee, H-W., Verlander, J.W. & Weiner, I.D. 2021. Role of the renal androgen receptor in sex differences in ammonia metabolism. American Journal of Physiology-Renal Physiology 321(5): F629-F644.

Institute for Public Health. 2023. Technical Report National Health and Morbidity Survey (NHMS) 2022: Maternal and Child Health. Malaysia: National Institutes of Health.

Kang, L.S., Masilamani, S. & Boegehold, M.A. 2016. Juvenile growth reduces the influence of epithelial sodium channels on myogenic tone in skeletal muscle arterioles. Clinical and Experimental Pharmacology and Physiology 43(12): 1199-1207.

Ledwoż, A., Michalak, J., Stȩpień, A. & Ka̧dziołka, A. 1986. The relationship between plasma triglycerides, cholesterol, total lipids and lipid peroxidation products during human atherosclerosis. Clinica Chimica Acta 155(3): 275-283.

Liu, Q., Wang, Y., Chen, Z., Guo, X. & Lv, Y. 2021. Age-and sex-specific reference intervals for blood urea nitrogen in Chinese general population. Scientifc Reports 11(1): 10058.

Long, L., Zhang, X., Wen, Y., Li, J., Wei, L., Cheng, Y., Liu, H., Chu, J., Fang, Y., Xie, Q., Shen, A. & Peng, J. 2022.  Qingda granule attenuates angiotensin ii-induced renal apoptosis and activation of the p53 pathway. Front. Pharmacol. 12: 770863.

Malta, A., de Oliveira, J.C., Ribeiro, T., Tófolo, L.P., Barella, L.F., Prates, K.V., Miranda, R.A., Elmhiri, G., Franco, C. & Agostinho, A.R. 2014. Low-protein diet in adult male rats has long-term effects on metabolism. Journal of Endocrinology 221(2): 285-295.

Michael, H., Amimo, J.O., Rajashekara, G., Saif, L.J. & Vlasova, A.N. 2022. Mechanisms of kwashiorkor-associated immune suppression: Insights from human, mouse, and pig studies. Front. Immunol. 13: 826268. 

Mısırlıoğlu, M., Yıldızdaş, D., Ekinci, F., Horoz, Ö.Ö., Özkale, Y., Özkale, M., Yöntem, A., Arslan, İ. & Tümgör, G. 2023. The effects of protein intake on clinical outcome in pediatric intensive care units. Turkish Archives of Pediatrics 58(1): 68.

National Health Service. 2022. What is weaning? https://www.nhs.uk/start-for-life/baby/weaning/ (Accessed on 13 April 2024).

Ou, H., Huang, Z., Mo, Z. & Xiao, J. 2017. The characteristics and roles of advanced oxidation protein products in atherosclerosis. Cardiovascular Toxicology 17(1): 1-12.

Pedroza, A., Ferreira, D.S., Santana, D.F., da Silva, P.T., de Aguiar Júnior, F.C.A., Sellitti, D.F. & Lagranha, C.J. 2019. A maternal low-protein diet and neonatal overnutrition result in similar changes to glomerular morphology and renal cortical oxidative stress measures in male Wistar rats. Applied Physiology, Nutrition, and Metabolism 44(2): 164-171.

Pezeshki, A., Zapata, R.C., Singh, A., Yee, N.J. & Chelikani, P.K. 2016. Low protein diets produce divergent effects on energy balance. Scientific Reports 6(1): 25145.

Sahoo, D.K., Heilmann, R.M., Paital, B., Patel, A., Yadav, V.K., Wong, D. & Jergens, A.E. 2023. Oxidative stress, hormones, and effects of natural antioxidants on intestinal inflammation in inflammatory bowel disease. Frontiers in Endocrinology 14: 1217165.

Smith, G.I. & Mittendorfer, B. 2016. Sexual dimorphism in skeletal muscle protein turnover. Journal of Applied Physiology 120(6): 674-682.

Snelson, M., Clarke, R.E., Nguyen, T.V., Penfold, S.A., Forbes, J.M., Tan, S.M. & Coughlan, M.T. 2021. Long term high protein diet feeding alters the microbiome and increases intestinal permeability, systemic inflammation and kidney injury in mice. Molecular Nutrition Food Research 65(8): 2000851.

Stamellou, E., Sterzer, V., Alam, J., Roumeliotis, S., Liakopoulos, V. & Dounousi, E. 2024. Sex-specific differences in kidney function and blood pressure regulation. International Journal of Molecular Sciences 25(16): 8637.

Theys, N., Clippe, A., Bouckenooghe, T., Reusens, B. & Remacle, C. 2009. Early low protein diet aggravates unbalance between antioxidant enzymes leading to islet dysfunction. PLoS ONE 4(7): e6110.

Uauy, R., Kurpad, A., Tano-Debrah, K., Otoo, G.E., Aaron, G.A., Toride, Y. & Ghosh, S. 2015. Role of protein and amino acids in infant and young child nutrition: Protein and amino acid needs and relationship with child growth. Journal of Nutrition Science Vitaminol 61(Supplement): S192-S194.

Valaei, K., Taherkhani, S., Arazi, H. & Suzuki, K. 2021. Cardiac oxidative stress and the therapeutic approaches to the intake of antioxidant supplements and physical activity. Nutrients 3(10): 3483.

Vega, C.C., Reyes‐Castro, L.A., Rodríguez‐González, G.L., Bautista, C.J., Vázquez‐Martínez, M., Larrea, F., Chamorro‐Cevallos, G.A., Nathanielsz, P.W. & Zambrano, E. 2016. Resveratrol partially prevents oxidative stress and metabolic dysfunction in pregnant rats fed a low protein diet and their offspring. Antioxidants 594(5): 1483-1499.

Wang, P., Yi, T., Mao, S. & Li, M. 2023. Neuroprotective mechanism of human umbilical cord mesenchymal stem cell‐derived extracellular vesicles improving the phenotype polarisation of microglia via the PI3K/AKT/Nrf2 pathway in vascular dementia. Synapse 77(4): e22268.

Wells, J.C. 2019. Body composition of children with moderate and severe undernutrition and after treatment: A narrative review. Wells BMC Medicine 17(1): 1-9.

Williamson, C. & Beatty, C. 2015. Weaning and childhood nutrition. InnovAiT: Education and Inspiration for General Practice 8(3): 141-145.

Witko-Sarsat, V., Friedlander, M., Capeillère-Blandin, C., Nguyen-Khoa, T., Nguyen, A.T., Zingraff, J., Jungers, P. & Descamps-Latscha, B. 1996. Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney International 49(5): 1304-1313.

World Health Organization. 2024. Malnutrition. https://www.who.int/news-room/fact-sheets/detail/malnutrition (Diakses pada April 13 2024).

Ying, M., Yang, J., Huang, Z., Ling, Y., Wang, B., Huang, H., Li, Q., Liu, J., Liu, Y. & Chen, Z. 2022. Association between malnutrition and contrast-associated acute kidney injury in congestive heart failure patients following coronary angiography. Frontiers in Nutrition 9: 937237.

*Pengarang untuk surat-menyurat; email: smlim@ukm.edu.my