RESUMO
In kidney disease renal proximal tubular epithelial cells (RPTEC) actively contribute to the progression of tubulointerstitial fibrosis by mediating both an inflammatory response and via epithelial-to-mesenchymal transition. Using laser capture microdissection we specifically isolated RPTEC from cryosections of the healthy parts of kidneys removed owing to renal cell carcinoma and from kidney biopsies from patients with proteinuric nephropathies. RNA was extracted and hybridized to complementary DNA microarrays after linear RNA amplification. Statistical analysis identified 168 unique genes with known gene ontology association, which separated patients from controls. Besides distinct alterations in signal-transduction pathways (e.g. Wnt signalling), functional annotation revealed a significant upregulation of genes involved in cell proliferation and cell cycle control (like insulin-like growth factor 1 or cell division cycle 34), cell differentiation (e.g. bone morphogenetic protein 7), immune response, intracellular transport and metabolism in RPTEC from patients. On the contrary we found differential expression of a number of genes responsible for cell adhesion (like BH-protocadherin) with a marked downregulation of most of these transcripts. In summary, our results obtained from RPTEC revealed a differential regulation of genes, which are likely to be involved in either pro-fibrotic or tubulo-protective mechanisms in proteinuric patients at an early stage of kidney disease.
Assuntos
Células Epiteliais/metabolismo , Nefropatias/metabolismo , Túbulos Renais Proximais/metabolismo , Proteinúria/metabolismo , Idoso , Apoptose/genética , Proteína Morfogenética Óssea 7 , Proteínas Morfogenéticas Ósseas/metabolismo , Estudos de Casos e Controles , Adesão Celular/genética , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular/genética , Proliferação de Células , Feminino , Perfilação da Expressão Gênica , Humanos , Fatores Imunológicos/metabolismo , Nefropatias/genética , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Proteinúria/genética , Transdução de Sinais/genética , Trombospondinas/metabolismo , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
Ischemic peripheral neuropathy is a frequent, irreversible complication of lower extremity vascular insufficiency. We investigated whether ischemic peripheral neuropathy could be prevented and/or reversed by gene transfer of an endothelial cell mitogen designed to promote therapeutic angiogenesis. Intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor (VEGF) simultaneously with induction of hindlimb ischemia in rabbits abrogated the substantial decrease in motor and sensory nerve parameters, and nerve function recovered promptly. When gene transfer was administered 10 days after induction of ischemia, nerve function was restored earlier and/or recovered faster than in untreated rabbits. These findings are due in part to enhanced hindlimb perfusion. In addition, however, the demonstration of functional VEGF receptor expression by Schwann cells indicates a direct effect of VEGF on neural integrity as well. These findings thus constitute a new paradigm for the treatment of ischemic peripheral neuropathy.
