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

Abstract

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.

Keywords: Immune system; Lung injury; Metabolismx; Microbiota.

Figure 1.. Hypoxia-inducible factors (HIFs) and immune cells.

(A) HIFs regulate immune cells by interfering with their metabolic pathways and function/phenotype. In neutrophils, HIF-1α activation favors glycolysis, increasing the cellular phagocytic capacity, surveillance, and release of neutrophil extracellular traps (NET). In natural killer (NK) cells, HIF-1α is associated with the balance between antibacterial function and tissue repair. HIF-1α increases the migration capacity of both eosinophils and dendritic cells (DCs). In pro-inflammatory macrophage (M1), HIF-1α is fundamental for the activation of glycolysis and pentose phosphate pathways (PPP) and increases the phagocytic capacity and nitric oxide synthase 2 (NOS2) expression, while suppressing oxidative phosphorylation (OXPHOS). HIF-2α is associated with higher tissue repair capacity through arginase-1 expression and lower glycolysis in anti-inflammatory macrophage (M2), which rely on OXPHOS to meet their energy demands. (B) HIF pathways balance the expression of transcriptional factors and effector functions in adaptive immunity. HIF-1α downregulates forkhead box P3 (Foxp3) and upregulates the retinoid orphan receptor gamma t (RORγt) in CD4⁺ T cells, interfering with their immune functions. During Th1 differentiation, HIF-1α increases the expression of interferon gamma (IFN-γ). In CD8⁺ T cells, HIF is associated with increased release of granzyme B and perforin and enhanced glycolytic activity. In B cells, HIF induces glycolysis, antibody production, and proliferation and inhibits apoptosis.

Figure 2.. Hypoxia-inducible factors (HIFs) in the lung-kidney and gut-kidney axes.

Increased systemic inflammation is associated with a higher risk of renal failure in patients with chronic obstructive pulmonary disease. Presence of kidney disease increases neutrophilia in bronchoalveolar lavage fluid and the levels of monocyte chemoattractant protein-1 (MCP-1), cytokines, and apoptosis in the lungs. HIF activation induces the expression of the antioxidant enzyme heme oxygenase 1, which can reduce the injury to the damaged lungs and kidneys. Renal damage also results in accumulation of uremic toxins, which promote intestinal dysbiosis and inflammation. Gut dysbiosis and lesions on the intestinal epithelium increase the passage of inflammatory molecules from the gut to circulation, reaching the kidneys, where they promote inflammation and dysfunction. A balanced gut microbiota produces short-chain fatty acids (SCFAs), which are increased by HIF activation and exert positive effects on the intestinal mucosa and immunity and reduce kidney inflammation. Therefore, kidneys, gut, and lungs receive a large blood supply, resulting in high exposure to circulating immune cells and molecules. HIFs can interfere with cell metabolism and the expression of cytokines by immune and epithelial cells, increasing the possibility that HIFs play a role in the lung-kidney and gut-kidney axes. However, it remains unclear whether HIF activation is beneficial or acts as a link between the diseases. GFR, glomerular filtration rate.