Navegando por Palavras-chave "Uretero-pelvic stenosis"

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    Estágio de desenvolvimento renal tem papel fundamental na fisiopatologia da uropatia obstrutiva
    (Universidade Federal de São Paulo (UNIFESP), 2017-10-25) Geminiani, Julio José [UNIFESP]; Ribeiro, Cassio Andreoni [UNIFESP]; http://lattes.cnpq.br/2915020488175752; http://lattes.cnpq.br/2801196536985579; Universidade Federal de São Paulo (UNIFESP)
    INTRODUCTION: Inflammation and fibrosis are widely accepted as the key processes driving the progression of obstruction-induced renal injuries to kidney disease in the mature kidney. However, it is likely that there are significant differences in the developing kidney, which have important implications for the treatment of congenital urinary tract obstruction. In this study, we provide the first direct comparison of injury responses during each of the critical stages of kidney development. METHODS: Disease progression was examined in a murine model of unilateral ureteral obstruction (UUO) at (1) P1, during nephrogenesis/nephron maturation and corresponding to the third trimester in humans, (2) P14, during the proliferative growth phase and corresponding to 1-2 years of infancy in humans, and (3) P60, in the mature kidney. Renal pathology was evaluated by performing immunostaining for molecular markers of key processes in the pathogenesis of renal injury and kidney development. The activation of pro-fibrotic signaling pathways and nephron differentiation programs was assessed by using quantitative PCR to monitor changes in gene expression. RESULTS: UUO at either P1 or P14 in the developing kidney leads to decreased kidney growth, reduced proliferative expansion of nephrons, increased apoptosis in progenitor cells, and impaired nephron differentiation. However, there is a notable absence of fibroblast and macrophage recruitment, inflammation, and fibrosis in the developing kidney following injury. This starkly contrasts the mature kidney where there are dramatic increases in proliferation, inflammation, and fibrosis following injury. In comparing these distinct outcomes at the molecular level, we found that injury responses in the developing kidney are characterized by the inhibition of nephron differentiation programs rather than the activation of pro-fibrotic signaling pathways (TGF-b, Renin-Angiotensin, WNT, PDGF) previously implicated as potential therapeutic targets by studies performed in the mature kidney. CONCLUSIONS: This study reveals that developmental context has a significant impact on the pathogenesis of renal injuries. In contrast to the mature kidney, injury in the developing kidney is characterized by profound developmental deficits and a distinct absence of inflammation and fibrosis. This suggests the treatment of patients with obstructive uropathies can be optimized by tailoring therapeutic strategies that are specific to the developmental context. More aggressive surgical intervention at early developmental stages may be necessary to prevent impaired renal maturation. Additionally, it may be beneficial to design adjuvant therapies to stimulate proliferation and minimize apoptosis at early stages of development while targeting inflammation and fibrosis at later stages of development.