Insulin-like growth factors and their carrier proteins in kidneys of rats with experimental diabetes, malignant tumor, and their combination

Persistent hyperglycemia resulting from diabetes mellitus causes microvascular lesions and long-term diabetic complications, such as nephropathy.

The aim of the study was to analyze the levels of insulin-like growth factors (IGFs), their carrier proteins (IGFBP), and markers of kidney tissue damage (IL-18, L-FABP, cystatin C, NGAL, and KIM-1) in male rats with diabetes mellitus, tumor growth, and their combination.

Materials and methods. The study included white outbred male rats (n = 32) weighing 180–220 g. The animals were divided into four groups (n = 8 each): group 1 – intact animals; controls (2) – animals with diabetes mellitus; controls (3) – animals with Guerin carcinoma; experimental group (4) – animals with Guerin carcinoma against the background of diabetes mellitus. Levels of IGF-1, IGF-2, IGFBP-1, IGFBP-2 and markers of acute kidney injury (IL-18, L-FABP, cystatin С, NGAL, and KIM-1) were determined in the kidney homogenates using enzyme-linked immunosorbent assay.

Results. Increased levels of acute kidney injury markers were found in the kidneys of male rats with diabetes mellitus alone and in combination with Guerin carcinoma. In the animals with diabetes mellitus, the levels of IGF-1, IGFBP-1, and IGFBP-2 were decreased on average by 1.3 times, and the level of IGF-2 was increased by 2.1 times compared with the values in the intact male rats. The elevation of IGF-2 / IGF-1 on average by 2.8 times indicated increasing hypoglycemia in the kidney tissue of the animals with diabetes mellitus and in the experimental group with diabetes mellitus and Guerin carcinoma. In the kidney tissues of the rats with Guerin carcinoma, IGF-1 and IGF-2 were elevated on average by 1.5 times, and IGFBP-2 was decreased by 1.7 times. In the animals with malignant tumors growing against the background of diabetes mellitus, IGF-2 and IGFBP-1 were increased by 2.3 and 1.7 times, respectively, and the levels of IGF-1 and IGFBP-2 were similar to those in the intact animals.

Conclusion. The study demonstrated abnormalities in the metabolic profile of the kidneys in male rats with experimental diabetes mellitus, Guerin carcinoma, and their combination.

1. Federation ID. IDF Diabetes Atlas. 9th. Brussels: Belgium: International Diabetes Federation, 2019.

2. Roy A., Maiti A., Sinha A., Baidya A., Basu A.K., Sarkar D. et al. Kidney Disease in Type 2 Diabetes Mellitus and Benefits of Sodium-Glucose Cotransporter 2 Inhibitors: A Consensus Statement. Diabetes Ther. 2020;11(12):2791–2827. DOI: 10.1007/s13300-020-00921-y.

3. Wang J., Yue X., Meng C., Wang Z., Jin X., Cui X. et al. Acute Hyperglycemia May Induce Renal Tubular Injury Through Mitophagy Inhibition. Front Endocrinol. (Lausanne). 2020;11:536213. DOI: 10.3389/fendo.2020.536213.

4. Romagnani P., Remuzzi G., Glassock R., Levin A., Jager K. Tonelli M. et al. Chronic kidney disease. Nature Reviews Disease Primers. 2017;3(1, article 17088). DOI: 10.1038/nrdp.2017.88.

5. Burton D.G.A., Faragher R.G.A. Obesity and type-2 diabe tes as inducers of premature cellular senescence and ageing. Biogerontology. 2018;19(6):447–459. DOI: 10.1007/s10522018-9763-7.

6. Martinez C.J., Sangros G.J., Garcia S.F., Millaruelo J.M. Chronic renal disease in Spain: prevalence and related factors in persons with diabetes mellitus older than 64 years. Nefrología. 2018;38:401–413.

7. Gao L., Zhong X., Jin J., Li J., Meng X.M. Potential targeted therapy and diagnosis based on novel insight into growth factors, receptors, and downstream effectors in acute kidney injury and acute kidney injury-chronic kidney disease progression. Signal Transduct. Target Ther. 2020;5(1):9. DOI: 10.1038/s41392-020-0106-1.

8. Solarek W., Koper M., Lewicki S., Szczylik C., Czarnecka A.M. Insulin and insulin-like growth factors act as renal cell cancer intratumoral regulators. Journal of Cell Communication and Signaling. 2019;13(3):381–394. DOI: 10.1007/s12079-01900512-y.

9. Bach L.A., Hale L.J. Insulin-like growth factors and kidney disease. Am. J. Kidney Dis. 2015;65(2):327–336. DOI: 10.1053/j.ajkd.2014.05.024.

10. Wu Z., Yu Y., Niu L., Fei A., Pan S. IGF-1 protects tubular epithelial cells during injury via activation of ERK/MAPK signaling pathway. Sci. Rep. 2016;6:28066. DOI: 10.1038/srep28066.

11. Wasung M.E., Chawla L.S., Madero M. Biomarkers of renal function, which and when? Clin. Chim. Acta. 2015;438:350– 357. DOI: 10.1016/j.cca.2014.08.039.

12. Darawshi S., Yaseen H., Gorelik Y., Faor C., Szalat A., Abassi Z. et al. Biomarker evidence for distal tubular damage but cortical sparing in hospitalized diabetic patients with acute kidney injury (AKI) while on SGLT2 inhibitors. Renal Failure. 2020;42(1):836–844. DOI: org/10.1080/0886022X.2020.1801466.

13. Abassi Z., Rosen S., Lamothe S., Heyman S.N. Why have detection, understanding and management of kidney hypoxic injury have lagged behind those for the heart? JCM. 2019;8(2):267.

14. Gohda T., Kamei N., Koshida T., Kubota M., Tanaka K., Yamashita Y. et al. Circulating kidney injury molecule-1 as a biomarker of renal parameters in diabetic kidney disease. J. Diabetes Investig. 2020;11(2):435–440. DOI: 10.1111/jdi.13139.

15. Жукова Г.В., Шихлярова А.И., Сагакянц А.Б., Протасова Т.П. О расширении вариантов использования мышей BALB/cnude для экспериментального изучения злокачественных опухолей человека in vivo. Южно-Российский онкологический журнал. 2020;1(2):28–35. DOI: org/10.37748/2687-0533-2020-1-2-

16. Livingston C. IGF2 and cancer. Endocr. Relat. Cancer. 2013;0(6):R32–1339. DOI: 10.1530/ERC-13-0231.

17. Wasnik S., Tang X., Bi H., Abdipour A., Carreon E., Sutjiadi B. et al. IGF-1 deficiency rescue and intracellular calcium blockade improves survival and corresponding mechanisms in a mouse model of acute kidney injury. Int. J. Mol. Sci. 2020;21(11):4095. DOI: 10.3390/ijms21114095.

18. Kashani K., Cheungpasitporn W., Ronco C. Biomarkers of acute kidney injury: the pathway from discovery to clinical adoption. Clin. Chem. Lab. Med. 2017;55(8):1074–1089. DOI: 10.1515/cclm-2016-0973.

19. Karim C.B., Espinoza-Fonseca L.M., James Z.M., Hanse E.A., Gaynes J.S., Thomas D.D. et al. Structural Mechanism for Regulation of Bcl-2 protein Noxa by phosphorylation. Sci. Rep. 2015;5:14557. DOI: 10.1038/srep14557.

20. Wang M., Yang Y., Liao Z. Diabetes and cancer: Epidemiological and biological links. World Journal of Diabetes. 2020;11(6):227–238. DOI: 10.4239/wjd.v11.i6.227.

21. Parikh C.R., Mansour S.G. Perspective on clinical application of biomarkers in AKI. J. Am. Soc. Nephrol. 2017;28(6):1677– 1685.

22. Medic B., Rovcanin B., Vujovic K.S., Obradovic D., Duric D., Prostran M. Evaluation of novel biomarkers of acute kidney injury: the possibilities and limitations. Curr. Med. Chem. 2016;23:1981–1997.

23. Schrezenmeier E.V., Barasch J., Budde K., Westhoff T., Schmidt-Ott K.M. Biomarkers in acute kidney injury – pathophysiological basis and clinical performance. Acta Physiol. (Physiol.). 2017;219:554–572.

24. Imai N., Yasuda T., Kamijo-Ikemori A., Shibagaki Y., Kimura K. Distinct roles of urinary liver-type fatty acid-binding protein in non-diabetic patients with anemia. PLoS One. 2015;10(5):e0126990.

25. Oh D.J. A long journey for acute kidney injury biomark ers. Renal Failure. 2020;42(1):154–165. DOI: 10.1080/0886022X.2020.1721300.

26. Кит О.И., Франциянц Е.М., Димитриади С.Н., Каплие ва И.В., Трепитаки Л.К. Экспрессия молекулярных маркеров острого повреждения почек в динамике экспериментальной ишемии. Экспериментальная и клиническая урология. 2014;(4):12–15.

27. Кит О.И., Франциянц Е.М., Димитриади С.Н., Каплие ва И.В., Трепитаки Л.К., Черярина Н.Д. и др. Роль маркеров острого повреждения почек в выборе тактики хирургического лечения больных раком почки. Онкоурология. 2015;11(3):34–39.