Reference - Detail
| RRC ID | 57680 |
|---|---|
| Author | Wang Y, Fang Q, Jin Y, Liu Z, Zou C, Yu W, Li W, Shan X, Chen R, Khan Z, Liang G. |
| Title | Blockade of myeloid differentiation 2 attenuates diabetic nephropathy by reducing activation of the renin-angiotensin system in mouse kidneys. |
| Journal | Br J Pharmacol |
| Abstract |
BACKGROUND AND PURPOSE:Both innate immunity and the renin-angiotensin system (RAS) play important roles in the pathogenesis of diabetic nephropathy (DN). Myeloid differentiation factor 2 (MD2) is a co-receptor of toll-like receptor 4 (TLR4) in innate immunity. While TLR4 is involved in the development of DN, the role of MD2 in DN has not been characterized. It also remains unclear whether the MD2/TLR4 signalling pathway is associated with RAS activation in diabetes. EXPERIMENTAL APPROACH:MD2 was blocked using siRNA or the low MW inhibitor, L6H9, in renal proximal tubular cells (NRK-52E cells) exposed to high concentrations of glucose (HG). In vivo, C57BL/6 and MD2-/- mice were injected with streptozotocin to induce Type 1 diabetes and nephropathy. KEY RESULTS:Inhibition of MD2 by genetic knockdown or the inhibitor L6H9 suppressed HG-induced expression of ACE and angiotensin receptors and production of angiotensin II in NRK-52E cells, along with decreased fibrosis markers (TGF-β and collagen IV). Inhibition of the MD2/TLR4-MAPKs pathway did not affect HG-induced renin overproduction. In vivo, using the streptozotocin-induced diabetic mice, MD2 was overexpressed in diabetic kidney. MD2 gene knockout or L6H9 attenuated renal fibrosis and dysfunction by suppressing local RAS activation and inflammation. CONCLUSIONS AND IMPLICATIONS:Hyperglycaemia activated the MD2/TLR4-MAPKs signalling cascade to induce renal RAS activation, leading to renal fibrosis and dysfunction. Pharmacological inhibition of MD2 may be considered as a therapeutic approach to mitigate DN and the low MW inhibitor L6H9 could be a candidate for such therapy. |
| Volume | 176(14) |
| Pages | 2642-2657 |
| Published | 2019-7-1 |
| DOI | 10.1111/bph.14687 |
| PMID | 30959575 |
| PMC | PMC6592858 |
| MeSH | Animals Cells, Cultured Chalcone / pharmacology* Diabetes Mellitus, Experimental / chemically induced Diabetes Mellitus, Experimental / drug therapy* Diabetes Mellitus, Experimental / immunology Diabetes Mellitus, Type 1 / chemically induced Diabetes Mellitus, Type 1 / drug therapy* Diabetes Mellitus, Type 1 / immunology Diabetic Nephropathies / chemically induced Diabetic Nephropathies / drug therapy* Diabetic Nephropathies / immunology Kidney / drug effects Kidney / immunology Lymphocyte Antigen 96 / antagonists & inhibitors* Lymphocyte Antigen 96 / deficiency Lymphocyte Antigen 96 / immunology Mice Mice, Inbred C57BL Mice, Knockout RNA, Small Interfering / pharmacology* Renin-Angiotensin System / drug effects Renin-Angiotensin System / immunology Streptozocin |
| IF | 7.73 |
| Times Cited | 3 |
| Resource | |
| Mice | RBRC02388 |