Abstract
The pathogenesis of chronic kidney disease (CKD) is complex and apparently multifactorial. Hypoxia or decrease in oxygen supply in kidney tissues has been implicated in CKD. Hypoxia inducible factors (HIF) are a small family of transcription factors that are mainly responsive to hypoxia and mediate hypoxic response. HIF plays a critical role in renal fibrosis during CKD through the modulation of gene transcription, crosstalk with multiple signaling pathways, epithelial-mesenchymal transition, and epigenetic regulation. Moreover, HIF also contributes to the development of various pathological conditions associated with CKD, such as anemia, inflammation, aberrant angiogenesis, and vascular calcification. Treatments targeting HIF and related signaling pathways for CKD therapy are being developed with promising clinical benefits, especially for anemia. This review presents an updated analysis of hypoxia response, HIF, and their associated signaling network involved in the pathogenesis of CKD.
Highlights
Chronic kidney disease (CKD) is a condition characterized by the gradual loss of kidney function over time
Due to the lack of information about Hypoxia inducible factors (HIF)-3 in kidney, in the current article we mainly focus on the regulation and function of HIF-1 and HIF-2 in CKDs
Hypoxia or HIF-induced epithelial-to-mesenchymal transition (EMT) is a well-known phenomenon in renal fibrosis in CKD conditions [45,60,64,72,73,74]
Summary
Chronic kidney disease (CKD) is a condition characterized by the gradual loss of kidney function over time. Elevated epithelial HIF-1α levels exacerbate the progression of kidney damage and renal fibrosis in a rat model of hypertension induced by high-salt diet and nitric oxide withdrawal [47] This evidence implies that activation of HIF-1α signaling in renal epithelial cells may accelerate fibrogenesis in CKD. HIF-1α is induced along with fibrotic markers and transdifferention markers, including collagen I/III, the tissue inhibitor of metalloproteinase-1 (TIMP1), vimentin, and alpha-smooth muscle actin(α-SMA) [50] Both in UUO model and in kidney ischemia model, ablation of HIF-1α in podocytes is protective against glomerulosclerosis and glomerular type-I collagen accumulation in mice [51].
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