Hypoxia promotes fibrogenesis in human renal fibroblasts

Abstract

Hypoxia promotes fibrogenesis in human renal fibroblasts. indicator of progression [3]. Tubulointersititial fibrosisBackground. The mechanisms underlying progressive renal is characterized by tubular dilation and atrophy, an infibrosis are unknown, but the common association of fibrosis crease in interstitial cell number, activation of fibroblasts and microvascular loss suggests that hypoxia per se may be a to myofibroblasts with increased expression of ␣-smooth fibrogenic stimulus.muscle actin (␣-SMA), obliteration of the microvascula-Methods. To determine whether human renal fibroblasts (HRFs), the primary matrix-producing cells in the tubulointersture, and accumulation of extracellular matrix (ECM) titium, possess oxygen-sensitive responses relevant to fibro-[1-5]. Despite the large number of studies documenting genesis, cells were exposed to 1% O 2 in vitro. changes in a variety of ECM proteins and growth factors, Results. Hypoxia simultaneously stimulated extracellular most notably transforming growth factor-␤1 (TGF-␤1) matrix synthesis and suppressed turnover with increased pro-[5, 6], in models of PRD and in human pathologies, the duction of collagen ␣1(I) (Coll-I), decreased expression of collagenase, and increased tissue inhibitor of metalloproteinase mechanisms underlying accumulation of ECM remain (TIMP)-1. These effects are time dependent, require new RNA obscure. In trying to understand the association of gloand protein synthesis, and are specific to hypoxia. The changes merular damage, interstitial fibrosis, and tubular atrophy in Coll-I and TIMP-1 gene expression involve a heme-protein in PRD, we have proposed a sequence of events that O 2 sensor and protein kinase-and tyrosine kinase-mediated signaling. Although hypoxia induced transforming growth factor-␤1 ascribes a central role to microvascular compromise and (TGF-␤1), neutralizing anti-TGF-␤1-antibody did not block hypoxia in the pathogenesis of interstitial fibrosis [7, 8]. hypoxia-induced Coll-I and TIMP-1 mRNA expression. Fur-Hypoxia can regulate expression of a wide variety thermore, hypoxic-cell conditioned-medium had no effect on of genes that may be induced or suppressed by either the expression of these mRNAs in naive fibroblasts, suggesting transcriptional and post-transcriptional mechanisms [redirect effects on gene transcription. Transient transfections identified a hypoxia response element (HRE) in the TIMP-1 viewed in 9-11]. Hypoxia response elements (HREs) promoter and demonstrated HIF-1-dependent promoter actihave been identified in the regulatory regions of a numvation by decreased ambient pO 2 .ber of genes and contain consensus binding sites for the Conclusions. These data suggest that hypoxia co-ordinately transcription factor hypoxia-inducible factor-1 (HIF-1) up-regulates matrix production and decreases turnover in renal [12][13][14]. A variety of other transcription factors are infibroblasts. The results support a role for hypoxia in the pathogenesis of fibrosis and provide evidence for novel, direct hypduced by low O 2 ,...

Lower haemoglobin level and subsequent decline in kidney function in type 2 diabetic adults without clinical albuminuria

“…Some of the explanations may be provided by in vitro and in vivo studies examining the effects of anaemia-induced renal hypoxia and oxidative stress. In culture cells, hypoxia has been found to increase mesangial/tubular cell extracellular matrix synthesis, leading to fibrogenic changes in the kidney by activating several gene transcripts including transforming growth factor-β (TGF-β), osteopontin, and the recently discovered hypoxia inducing factor-1 (HIF-1) [26,27]. Hypoxiainduced altered renal sympathetic nerve activity may differentially regulate glomerular haemodynamics [28].…”

Hypoxia and the HIF system in kidney disease

“…Tubular cells under hypoxic conditions undergo epithelial-mesenchymal transdifferentiation to become myofibroblasts [19]. Hypoxia can also activate fibroblasts and change the extracellular matrix metabolism of resident renal cells [20,21]. pH is another factor that is implicated in cell injury under hypoxia.…”

Anemia Management and the Delay of Chronic Renal Failure Progression

“…Hypoxia and overproduction of reactive oxygen species are two of the factors that promote the release of these proinflammatory and profibrotic molecules, as shown by in vitro studies (24 -26). Furthermore, hypoxia and reactive oxygen species directly enhance the synthesis of extracellular matrix by fibroblastic cells (27)(28)(29)(30)(31).…”

“…Thus, correcting anemia with epoetin should increase oxygen delivery to tubular cells, decrease tubular damage, and ultimately protect against nephron loss induced by tubular injury. Furthermore, because hypoxia stimulates the production of extracellular matrix by tubular cells and by renal interstitial fibroblasts, as well as the release of profibrotic cytokines such as TGF-␤, decreasing hypoxia should slow the rate of extracellular matrix accumulation (24,31). Part of the beneficial effects of epoetin on hypoxia may also be mediated through its proangiogenic properties (43,44), that will oppose the decrease in the number of interstitial capillaries.…”