Abstract
This study aimed to explore how Dab1 gene functional silencing influences the spatial and temporal expression patterns of fibroblast growth factor receptor 1 (FGFR1), fibroblast growth factor receptor 2 (FGFR2), receptor-interacting protein kinase 5 (RIP5), and huntingtin-interacting protein 2 (HIP2) in the developing and postnatal kidneys of the yotari mice as potential determinants of normal kidney formation and function. Dab1−/− animal kidneys exhibit diminished FGFR1/FGFR2 expression in all examined developmental stages, whereas RIP5 cell immunoreactivity demonstrated negligible variation. The HIP2 expression revealed a discernible difference during the postnatal period, where we noted a significant decrease in almost all the observed kidney structures of yotari animals. An extracellular signal-regulated kinase (Erk1/2) and mammalian target of rapamycin (mTOR) expression in yotari kidneys decreased in embryonic and postnatal developmental phases for which we can hypothesize that the Erk1/2 signaling pathway in the yotari mice kidneys is dependent on Reelin with Dab1 only partially implicated in Reelin-mediated MEK/Erk1/2 activation. The impairment of FGFR1 and FGFR2 expression suggests the involvement of the observed markers in generating the CAKUT phenotype resulting in renal hypoplasia. Our study demonstrates the critical role of HIP2 in reducing cell death throughout nephrogenesis and maturation in wild-type mice and indicates a possible connection between decreased HIP2 expression in postnatal kidney structures and observed podocyte injury in yotari. Our results emphasize the crucial function of the examined markers throughout normal kidney development and their potential participation in kidney pathology and diagnostics, where they might serve as biomarkers and therapeutic targets.
Highlights
Introduction iationsThe yotari (Dab1−/− ) mouse, an autosomal recessive mutant mouse, arose spontaneously during the generation of mice carrying a gene mutation encoding the receptor for inositol-1,4,5-trisphosphate [1]
The immunoexpression of fibroblast growth factor receptor 1 (FGFR1), fibroblast growth factor receptor 2 (FGFR2), and huntingtin-interacting protein 2 (HIP2) was analyzed on metanephric mesenchyme, renal vesicles, glomeruli (g), convoluted tubules (Ct), ampullae (A), and collecting ducts (Cd) at embryonic days E13.5 and E15.5, and glomeruli (G), proximal
Using a Dab1−/− mice model, we characterized the significant differences in spatio-temporal distribution patterns of FGFR1, FGFR2, receptor-interacting protein kinase 5 (RIP5), and HIP2, in both embryonic and postnatal developmental stages
Summary
The yotari (Dab1−/− ) mouse, an autosomal recessive mutant mouse, arose spontaneously during the generation of mice carrying a gene mutation encoding the receptor for inositol-1,4,5-trisphosphate [1]. The phenotype of the yotari, very similar to those of reeler (Reelin−/− ) mice, is characterized by unsteady gait, tremors, and premature death at the time of weaning [1]. Our latest research revealed the congenital anomalies of the kidney and urinary tract (CAKUT) phenotype resulting in renal hypoplasia followed by foot process effacement in the kidney glomeruli and loss of functional kidney tissue of yotari [2]. The data implicate chronic kidney disease (CKD) as the cause of yotari mice’s premature death, which can be propagated by various mechanisms that may influence the kidney structures [2,3]. The Disabled-1 (Dab1) protein has been found in mouse
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