The impact of hypoxia-inducible factors in the pathogenesis of kidney diseases: a link through cell metabolism.

Kidneys are sensitive to disturbances in oxygen homeostasis. Hypoxia and activation of the hypoxia-inducible factor (HIF) pathway alter the expression of genes involved in the metabolism of renal and immune cells, interfering with their functioning. Whether the transcriptional activity of HIF protects the kidneys or participates in the pathogenesis of renal diseases is unclear. Several studies have indicated that HIF signaling promotes fibrosis in experimental models of kidney disease. Other reports showed a protective effect of HIF activation on kidney inflammation and injury. In addition to the direct effect of HIF on the kidneys, experimental evidence indicates that HIF-mediated metabolic shift activates inflammatory cells, supporting the HIF cascade as a link between lung or gut damage and worsening of renal disease. Although hypoxia and HIF activation are present in several scenarios of renal diseases, further investigations are needed to clarify whether interfering with the HIF pathway is beneficial in different pathological contexts.

Aerobic exercise training engages cholinergic signaling to improve emphysema induced by cigarette smoke exposure in mice.

Lung inflammation is modulated by cholinergic signaling and exercise training protects mice against pulmonary emphysema development; however, whether exercise training engages cholinergic signaling is unknown. AIMS: As cholinergic signaling is directly linked to the vesicular acetylcholine transporter (VAChT) levels, we evaluated whether the effects of aerobic exercise training depend on the VAChT levels in mice with pulmonary emphysema. MAIN METHODS: Wild-type (WT) and mutant (KDHOM) mice (65-70% of reduction in VAChT levels) were exposed to cigarette smoke (30 min, 2×/day, 5×/week, 12 weeks) and submitted or not to aerobic exercise training on a treadmill (60 min/day, 5×/week, 12 weeks). Lung function and inflammation were evaluated. KEY FINDINGS: Cigarette smoke reduced body mass in mice (p < 0.001) and increased alveolar diameter (p < 0.001), inflammation (p < 0.001) and collagen deposition (p < 0.01) in lung tissue. Both trained groups improved their performance in the final physical test compared to the initial test (p < 0.001). In WT mice, exercise training protected against emphysema development (p < 0.05), reduced mononuclear cells infiltrate (p < 0.001) and increased MAC-2 positive cells in lung parenchyma (p < 0.05); however, these effects were not observed in KDHOM mice. The exercise training reduced iNOS-positive cells (p < 0.001) and collagen fibers deposition (p < 0.05) in lung parenchyma of WT and KDHOM mice, although KDHOM mice showed higher levels of iNOS-positive cells. SIGNIFICANCE: Our data suggest that the protective effects of aerobic exercise training on pulmonary emphysema are, at least in part, dependent on the integrity of the lung cholinergic signaling.