Abstract
Sphingosine kinase 1 (SphK1) plays a pivotal role in regulating diabetic renal fibrotic factors such as fibronectin (FN) and intercellular adhesion molecule-1 (ICAM-1). Especially, activation of SphK1 is closely linked to the body inflammatory reaction. Casein kinase 2α subunit (CK2α), a protein kinase related to inflammatory reaction, influences diabetic renal fibrosis and expressions of FN and ICAM-1 via NF-κB pathway. However, the mechanism by which SphK1 mediates diabetic renal fibrosis has not yet fully elucidated. The current study is aimed to investigate if SphK1 mediates diabetic renal fibrotic pathological process via inflammatory pathway and activation of CK2α. The following findings were observed: (1) Expressions of SphK1 were upregulated in kidneys of diabetic mice and rats; (2) Knockdown of SphK1 expression suppressed high glucose (HG)-induced NF-κB nuclear translocation and expressions of FN and ICAM-1; (3) Compared with C57 diabetic mice, SphK1-/- diabetic mice exhibited less renal fibrotic lesions, FN accumulation and NF-κB nuclear accumulation in glomeruli of kidneys; (4) SphK1 mediated phosphorylation of CK2α, while CK2α knockdown depressed SphK1-induced activation of NF-κB pathway. This study indicates the essential role of SphK1 in regulating activation of CK2α and diabetic renal fibrotic pathological process via NF-κB.
Highlights
Diabetic nephropathy (DN), known as diabetic glomerulosclerosis characterized by renal fibrosis, is a major chronic microvascular complication of diabetes mellitus (DM) and is the leading cause of morbidity and mortality in diabetic patients with end-stage renal failure [1, 2]
Previous studies suggest that Sphingosine kinase 1 (SphK1) appears to act as an oncogenic enzyme regulating various processes which is important in cancer progression and even shows physiological regulatory functions on antiapoptosis, transformation, proliferation, and survival of tumor cells [37,38,39]
Accumulating evidence suggests that SphK1 is closely associated with inflammation, cardiovascular system and immune system, affecting diabetic nephropathy, angiogenesis, vascular maturation, smooth muscle cell proliferation and immune inflammatory regulation [40,41,42]
Summary
Diabetic nephropathy (DN), known as diabetic glomerulosclerosis characterized by renal fibrosis, is a major chronic microvascular complication of diabetes mellitus (DM) and is the leading cause of morbidity and mortality in diabetic patients with end-stage renal failure [1, 2]. Accumulating evidence suggests that the pathological mechanism of diabetic renal fibrosis is complicated and closely related to numerous factors. Increasing number of studies suggest that inflammation is involved in the development and progression of DN, and it even receives serious attention that diabetic renal fibrotic disease is one kind of renal chronic inflammatory response [5,6,7]. Under non-diabetic state, IκB acts as an anchor protein to combine with NF-κB in the cytoplasm, forming an inactive complex to inhibit the activation of NF-κB signaling pathway. Further study about the molecular mechanism of diabetic renal fibrosis and inflammation is imperative for preventing the progression of diabetic renal failure and exploring an approach to DN treatment
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