Comprehensive Immunophenotypic Expression Analysis Of Phospholipid Binding Proteins In Renal Organogenesis And In Kidney Carcinoma

Abstract

Several studies on the mechanism of renal development indicate a close relationship between renal embryonic cells and renal cancer cells contributing to the diversity of morphologic patterns, molecular and immunohistochemical phenotypes of renal cancers. The normal human kidney develops from three sources; the metanephric blastema, ureteric bud and angiogenic mesenchyme. The development of the collecting and secretory components of human kidney require a controlled cellular proliferation, apoptosis, differentiation, cell-cell contacts and cell matrix interactions. One of the causes in the etiology of renal neoplasms is the mutation of molecules or the reactivation of repressed genes which have important role in nephrogenesis. Annexin A1 (AnxA1) and Annexin A2 (AnxA2) are multifuctional calcium regulated phospholipid binding proteins found in a subset of renal neoplasms. With varying concentration of Ca2+, they are considered to regulate several biological processes such as cell proliferation, apoptosis and differentiation. On account of these features, we analyzed the expression of these proteins in fetal kidney at different gestational periods, mature kidney and in kidney cancer tissues in order to possibly understand their biological role during nephrogenesis, functions in cells of mature kidney and understand renal tumors from the perspective of developmental biology.Objectives: a) To demonstrate the expression pattern of AnxA1 and AnxA2 in various renal structures of developing human fetal kidneys at different gestational ages. b) Expression analysis of AnxA1 and AnxA2 in renal carcinoma and normal renal tissue. c) To compare the expression pattern of AnxA1 and AnxA2 in various renal structures of developing human fetal kidneys, adult kidneys with those observed in renal carcinomatous tissues. Materials and Methods: AnxA1 and AnxA2 expression was investigated by immunohistochemistry technique in ―Paraffin-embedded‖ renal tissue sections from autopsied fetuses of gestational age ranging from 14 to 39 weeks, in mature kidneys (35-85yrs of age) and renal cancer tissues. Haematoxylin and eosin staining of renal tissues was performed to study the a) histogenesis of fetal kidney in various stages of fetal development b) normal histological architecture of mature kidney c) types of renal cell carcinomas and confirm the original diagnosis, before performing immunohistochemistry. Tumors were graded according to Fuhrman et al.Results: The current study data demonstrated that AnxA1 is expressed in the mesangial cells and podocytes of maturing glomeruli in the developing renal cortex of fetal kidneys at 14 to 19 weeks of gestational age. The expression in the mesangial cells declined at later weeks of gestation and persisted in adulthood. AnxA1 expression increased with the progression of clear cell renal cell carcinoma and other types of renal cell carcinoma indicating a potential role of the protein in tumorigenesis. The study showed moderate membranous expression of AnxA2 in the ureteric bud and collecting tubules of fetal kidneys in all gestational ages and in the collecting ducts of adult normal renal tissues. It is not often expressed in the proximal convoluted tubules of normal adult kidney; however younger fetal kidneys show moderate expression in the proximal convoluted tubules (thought to be the origin of renal cell carcinoma) and reappearance of strong membranous expression in the clear cell carcinoma suggesting a deregulation of the gene during tumorigenesis. Conclusion: Understanding the molecular expression pattern of AnxA1 and AnxA2 during development, later their specific function and deregulated expression in different renal carcinoma indicates the decisive role of these proteins in the cancer progression. These results and concepts provide a framework to further dissect biological properties of AnxA1 and AnxA2 and thereby develop diagnostic, prognostic and therapeutic strategies targeting the molecule in various renal pathologies.