THE KI-67 CELL PROLIFERATION MARKER IN HUMAN METANEPHROGENESIS

  • Milorad Antić Faculty of Medicine - University of Nis
  • Vladimir Antić Fakultet fizičke kulture i sporta, Niš, Srbija
  • Braca Kundalić Univerzitet u Nišu, Medicinski fakultet, Niš, Srbija
  • Miljana Pavlović Univerzitet u Nišu, Medicinski fakultet, Niš, Srbija
  • Vladimir Živković Univerzitet u Nišu, Medicinski fakultet, Niš, Srbija
Keywords: kidney development, metanephrogenesis, cell proliferation, Ki-67

Abstract


The kidney plays several essential roles, including the excretion of metabolic wastes, maintenance of key homeostatic parameters of the blood plasma, participation in blood pressure and hormone levels regulation. These diverse functions are enabled by the developmental process that provides the presence of specific cells for performing all diverse functions. Organogenesis of the kidney is an intricate mechanism involving cell proliferation as a fundamentally necessary process. The aim of this study was to determine proliferative activity during the metanephros stage of renal development, based on the spatial and temporal expression pattern of the cell proliferation marker Ki-67. Kidney tissue specimens of 30 human fetuses with gestational ages ranging from 11 to 36 weeks were analyzed. The specimens were divided into three groups based on gestational age, each corresponding to the earlier, mid or late gestation period. Routine histological processing yielded tissue sections. The proliferative activity of the cells (expression of the Ki-67 protein) was examined by an immunohistochemical assessment of Ki-67, according to the manufacturer's protocol. The presence of Ki-67-positive cells characterized all metanephric structures but with different intensity. The most prominent expression was revealed in the nephrogenic zone in the earlier weeks of development, indicating the role of cell proliferation in nephron formation. The intensity of Ki-67 antigen expression gradually decreased in all cortical structures until the end of the trial period. In the metanephric medulla, the proliferation was less pronounced only after week 20, and the only Ki-67 positive cells were single cells of collecting duct epithelia, narrow parts of Henle’s loops and the interstitium. Cell proliferation was continuously present during metanephrogenesis. It was characterized by different intensity, more pronounced in the nephrogenic zone and renal cortex due to the dominant presence of cells in their structural components. However, the obvious developmental remodeling of the kidney tissues inevitably indicates the need to correlate proliferation with other developmental processes, apoptosis above all.

References

Agilent Technologies. Monoclonal Mouse Anti-Human Ki-67 Antigen Clone MIB-1 [package insert]. Santa Clara, CA: Agilent Technologies; 2024. Available from: https://www.agilent.com/cs/library/packageinsert/public/Copy%20of%20SSM7240CEEFG_03.pdf

Antić M. Komparativna analiza imunohistohemijskih i histomorfometrijskih karakteristika humane metanefrogeneze [dissertation]. Niš: Medicinski fakultet Univerziteta u Nišu; 2022.

Carev D, Krnić D, Saraga M, Sapunar D, Saraga-Babić M. Role of mitotic, pro-apoptotic and anti-apoptotic factors in human kidney development. Pediatr Nephrol 2006;21(5):627-36. [CrossRef][PubMed]

Costantini F, Kopan R. Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. Dev Cell 2010;18(5):698-712. [CrossRef][PubMed]

Daković-Bjelaković M, Stefanović N, Vlajković S, Čukuranović R, Antić S, Bjelaković G at al. Human kidney development. Acta Fac Med Naiss 2004;21(3):163-70.

Davies JA. Morphogenesis of the Metanephric Kidney. The Scientific World Journal 2002;2:1937–50. [CrossRef][PubMed]

Dressler GR. Advances in early kidney specification, development and patterning. Development 2009;136:3863-74. [CrossRef][PubMed]

Dressler GR. The cellular basis of kidney development. Annu Rev Cell Dev Biol 2006;22:509–29. [CrossRef][PubMed]

Faa G, Gerosa C, Fanni D, Monga G, Zaffanello M, Van Eyken P, et al. Morphogenesis and molecular mechanisms involved in human kidney development. J Cell Physiol 2012;227(3):1257-68. [CrossRef][PubMed]

Faa G, Gerosa C, Fanni D, Nemolato S, Di Felice E, Van Eyken P, et al. The role of immunohistochemistry in the study of the newborn kidney. J Matern Fetal Neonatal Med 2012;25(Suppl 4):135-8. [CrossRef][PubMed]

Hinchliffe SA, Sargent PH, Howard CV, Chan YF, van Velzen D. Human intrauterine renal growth expressed in absolute number of glomeruli assessed by the disector method and Cavalieri principle. Lab Invest 1991;64(6):777–84. [PubMed]

Lindström NO, Tran T, Guo J, Rutledge E, Parvez RK, Thornton ME, et al. Conserved and Divergent Molecular and Anatomic Features of Human and Mouse Nephron Patterning. J Am Soc Nephrol 2018;29:825–40. [CrossRef][PubMed]

Little M, Georgas K, Pennisi D, Wilkinson L. Kidney development: two tales of tubulogenesis. Curr Top Dev Biol 2010;90:193-229. [CrossRef][PubMed]

Little MH, McMahon AP. Mammalian kidney development: principles, progress, and projections. Cold Spring Harb Perspect Biol 2012;4(5):a008300. [CrossRef][PubMed]

McEwen LC, Sutherland MR, Black MJ. The Human kidney: Parallels in structure, spatial development, and timing of nephrogenesis. In: Little MH, editor. Kidney development, disease, repair and regeneration. Cambridge (US): Academic Press; 2016. p. 27-40. [CrossRef]

Minuth WW. Shaping of the nephron - a complex, vulnerable, and poorly explored backdrop for noxae impairing nephrogenesis in the fetal human kidney. Mol Cell Pediatr 2020;7(1):2. [CrossRef][PubMed]

Moritz KM, Wintour EM, Black MJ, Bertram JF, Caruana G. Factors influencing mammalian kidney development: implications for health in adult life. Adv Anat Embryol Cell Biol 2008;196:1-78. [CrossRef][PubMed]

Nagalakshmi VK, Yu J. The ureteric bud epithelium: morphogenesis and roles in metanephric kidney patterning. Mol Reprod Dev 2015;82(3):151-66. [CrossRef][PubMed]

Pietilä I, Vainio SJ. Kidney Development: An Overview. Nephron Exp Nephrol 2014;126:40–4. [CrossRef][PubMed]

Pokarna DJ, Kshitija K, Saritha S. Histogenesis of human fetal kidney from 14 weeks to 36 weeks: a study. International Journal of Research in Medical Sciences 2019;7(11):4330-34. [CrossRef]

Puddu M, Fanos V, Podda F, Zaffanello M. The kidney from prenatal to adult life: perinatal programming and reduction of number of nephrons during development. Am J Nephrol 2009;30(2):162-70. [CrossRef][PubMed]

Reidy KJ, Rosenblum ND. Cell and molecular biology of kidney development. Semin Nephrol 2009;29(4):321-37. [CrossRef][PubMed]

Rosenblum ND. Developmental biology of the human kidney. Semin Fetal Neonatal Med 2008;13(3):125-32. [CrossRef][PubMed]

Ryan D, Sutherland MR, Flores TJ, Kent AL, Dahlstrom JE, Puelles VG, et al. Development of the Human fetal kidney from mid to Late gestation in male and female infants. EBioMedicine 2018; 27:275-83. [CrossRef][PubMed]

Short KM, Smyth IM. Branching morphogenesis as a driver of renal development. Anat Rec 2020;303(10):2578-87. [CrossRef][PubMed]

Short KM, Smyth IM. The contribution of branching morphogenesis to kidney development and disease. Nat Rev Nephrol 2016;12(12):754-67. [CrossRef][PubMed]

Tank KC, Saiyad SS, Pandya AM, Akbari VJ, Dangar KP. A study of histogenesis of human fetal kidney. Int J Biol Med Res 2012;3(1):1315-21.

Published
2025/02/07
Section
Original article