Immunohistochemical Expression Pattern of FGFR1, FGFR2, RIP5, and HIP2 in Developing and Postnatal Kidneys of Dab1−/− (yotari) Mice

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.

Immunoexpression Pattern of Autophagy Markers in Developing and Postnatal Kidneys of Dab1−/−(yotari) Mice

“…These malformations are the most common congenital disabilities and the leading cause of end-stage renal disease in children [ 38 , 39 ]. In our earlier research with yotari mice, we discovered a series of different markers and how disruption in one step of their signaling pathways can result in CAKUT [ 11 , 40 , 41 ].…”

Aberrations in FGFR1, FGFR2, and RIP5 Expression in Human Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)

“…So far, monogenic disorders related to CAKUT involve mutations in 23 genes and have been identified in a small percentage (12%) of examined cases, with insufficient evidence of their causative role [ 7 ]. This research aimed to investigate the spatio-temporal expression of RIP5 , a new CAKUT candidate [ 9 ], and FGFR1 , and FGFR2 , well-known potential candidate genes, in developing human kidneys and kidneys affected with congenital anomalies [ 12 , 13 ].…”

“…Our earlier studies on human kidneys showed RIP5 expression in early human kidney development from the 5th to 22nd dw, noticed first in the undifferentiated metanephric mesenchyme [ 12 ]. We found a notable membrane-associated distribution of RIP5 in mesenchymal-derived cells in mice kidney development (E15.5) [ 9 , 13 ]. We also showed RIP5, FGFR1, and FGFR2 expression patterns, which decreased during human kidney development from the 6th to the 22nd developmental week [ 12 ].…”

“…Expression dynamics and progression of the percentage of the RIP5-positive cells in DU, HYP, and DYS kidneys revealed a gradual decrease over observed dw, as opposed to CTRL, which demonstrated a linear growth with time. The significance of RIP5 in the initial stages of nephrogenesis and maturation and, along with FGFR1 and FGFR2, in vasculogenesis is already familiar [ 12 , 13 ]. We hypothesize that the expression of RIP5 during normal human kidney development reduces temporarily due to urine production and increases later since it undertakes additional functions in the maturation of the postnatal kidney and homeostasis.…”

“…In the fetal kidney, RIP5 and FGFRs are co-expressed in the metanephric mesenchyme and ureteric bud, thus making RIP5 a critical regulator of human urinary system development downstream of Fibroblast Growth Factor (FGF) signaling [ 9 , 11 , 12 , 13 ]. In human embryonic kidney cell culture, RIP5 knockdown inhibits FGF-stimulated phosphorylation of Extracellular Signal-Regulated Kinase (ERK), the most important signal downstream of receptor tyrosine kinases [ 9 ].…”