Bradykinin mediates the association of collecting duct cells to form migratory colonies, through B2 receptor activation

Abstract

It is known that bradykinin (BK) B2 receptor (B2R) is expressed in the collecting duct (CD) cells of the newborn rat kidney, but little is known about its role during early postnatal life. Therefore, we hypothesize that BK could participate in the mechanisms that mediate CD formation during the postnatal renal development. Performing primary cultures, combined with biochemical, immunocytochemical, and time-lapse analysis, we studied the role of BK in CD cell behavior isolated from renal papilla of neonatal rats. A reverse relationship was observed between B2R expression and the degree of CD epithelial cell sheet maturation. BK stimulation induced CD cell association upon B2R activation. The lack of B2R expression in cells showing mature adherens junctions suggested that BK is mostly involved in early adhesive events, thus favoring the initial formation of CD during development. Time-lapse analysis revealed that BK induced a high protrusive activity of CD cells, denoted by ruffle formation and lamellipodia extension. PI3K was involved in the BK-induced CD cell-cell association and the acquisition of the migratory phenotype since, when inhibited, membrane ruffles, and filopodia between cells diminished. Results indicate that the actions of BK mediated by PI3K activation were due to the downstream Akt and Rac pathways. This study, performed with CD cells that were not genetically manipulated, provides new experimental evidence supporting a novel role of BK in rat renal CD organization. As B2R blockade results in abnormal tubular differentiation, our results contribute to better understanding the etiology of human congenital renal malformation and diseases.

Roscovitine blocks collecting duct cyst growth in Cep164-deficient kidneys

“…Why roscovitine failed to inhibit cyst growth in the medullary collecting ducts remains unclear. Given that the morphogenesis of different collecting duct segments is differentially regulated by local cues and cellular factors during postnatal kidney growth, [27][28][29] it is likely that roscovitine does not target all of these mechanisms. Also, it is plausible that the roscovitine dosing schedule used here (every 24 hours) does not provide sustained inhibition to the hyperproliferation of the medullary collecting duct cells that have endogenously high proliferative capacity during normal kidney growth 27 or that timing of roscovitine treatment was too late, as the first medullary cysts were present already at P7.…”

Novel cellular mechanism that mediates the collecting duct formation during postnatal renal development

“…In newborn rat kidneys, bradykinin B2 receptor (B2R) gene expression is highly activated, being 30-to 40-fold higher than in adult rat kidneys (El-Dahr, Figueroa, Gonzalez, & Müller-Esterl, 1997; | 13395 Yosipiv, Dipp, & El-Dahr, 1997). We have previously demonstrated that B2R expression is inversely related to the intensity of DBA staining, and thus to the degree of CD cell maturation (Guaytima et al, 2018). To analyze in more detail the characteristics and distribution of the cells that express this receptor, 3D reconstructions of optical sections of the monolayer and xz profile were obtained.…”

“…α-SMA: α-smooth muscle actin; BSL-I: Griffonia (Bandeiraea) Simplicifolia lectin-I; CD: collecting duct; CK7: cytokeratin 7; DBA: Dolichos biflorus agglutinin a cytosolic cytokeratin 7 signalYosipiv, Dipp, & El-Dahr, 1997). We have previously demonstrated that B2R expression is inversely related to the intensity of DBA staining, and thus to the degree of CD cell maturation(Guaytima et al, 2018). To analyze in more detail the characteristics and distribution of the cells that express this receptor, 3D reconstructions of optical sections of the monolayer and xz profile were obtained.…”