sphingosine-1-phosphate and Glomerulonephritis--IGA

Because the association between sphingosine 1-phosphate (S1P)/apolipoprotein M (ApoM) and chronic kidney diseases has not been established, we investigated the involvement of S1P/ApoM in the phenotypes of IgA nephropathy in hyper-IgA (HIGA) mice. The overexpression of ApoM in adenoviral gene transfer ameliorated the phenotypes of IgA nephropathy in HIGA mice, whereas the knockdown of ApoM with siRNA caused deterioration. When ApoM-overexpressing HIGA mice were treated with VPC23019, an antagonist against S1P receptor 1 (S1P1) and 3 (S1P3), we observed that the protective effects of ApoM were reversed, whereas JTE013, an antagonist against S1P2, did not inhibit the effects. We also found that S1P bound to albumin accelerated the proliferation of MES13 cells and the fibrotic changes of HK2 cells, which were inhibited by JTE013, whereas S1P bound to ApoM suppressed these changes, which were inhibited by VPC23019. These results suggest that S1P bound to ApoM possesses properties protective against the phenotypes of IgA nephropathy through S1P1 and S1P3, whereas S1P bound to albumin exerts deteriorating effects through S1P2. ApoM may be useful as a therapeutic target to treat or retard the progression of IgA nephropathy.-Kurano, M., Tsuneyama, K., Morimoto, Y., Nishikawa, M., Yatomi, Y. Apolipoprotein M suppresses the phenotypes of IgA nephropathy in hyper-IgA mice.

Topics: Animals; Apolipoproteins M; Blotting, Western; Cell Line; Creatinine; Female; Glomerulonephritis, IGA; Immunoglobulin A; Lysophospholipids; Mice; Mice, Inbred BALB C; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Sphingosine; Sphingosine-1-Phosphate Receptors

Nephrokeli (NPKL) is a Chinese herbal formula that has been used to treat patients with IgA nephropathy (IgAN) for improvement of proteinuria and kidney injury. However, the mechanism remains unclear. Sphingosine-1-phosphate (S1P) and its receptors S1PR2 and S1PR3 are known to play an important role in kidney disease. Here, we tested whether NPKL is able to regulate the S1P pathway in the kidney of IgAN rats. Four groups of rats were included in the study: Control, IgAN, IgAN treated with losartan, and IgAN treated with NPKL. The IgAN model was generated by injection of bovine serum albumin and staphylococcus enterotoxin B. We found that IgAN rats had increased staining for proliferating cell nuclear antigen (PCNA) in the mesangial area and increased mRNA and protein levels of S1PR2 and S1PR3 in the kidney compared to control rats. Connective tissue growth factor (CTGF), a downstream growth factor in the S1P pathway, was also elevated in the kidney of IgAN rats. Treatment with either NPKL or losartan was able to reduce PCNA staining and the expression of both S1PR2 and S1PR3 in the kidney of IgAN rats. However, NPKL (but not losartan treatment) reduced the expression of CTGF in the kidney of IgAN rats. In addition, we treated rat mesangial cells with sera collected from either NPKL-treated rats or control rats and found that NPKL-serum was able to reduce S1P-induced mesangial cell proliferation and the expression of S1PR2/S1PR3 and CTGF. NPKL also attenuates expression of fibrosis, inflammation, and oxidative stress markers in the kidney of IgAN rats. Our studies provide the mechanism by which NPKL attenuates kidney injury in IgAN rats.

Topics: Animals; Drugs, Chinese Herbal; Female; Glomerulonephritis, IGA; Kidney; Lysophospholipids; Rats; Rats, Sprague-Dawley; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors