| First Author | Omote K | Year | 2014 |
| Journal | Am J Physiol Renal Physiol | Volume | 306 |
| Issue | 11 | Pages | F1335-47 |
| PubMed ID | 24647715 | Mgi Jnum | J:210977 |
| Mgi Id | MGI:5572989 | Doi | 10.1152/ajprenal.00509.2013 |
| Citation | Omote K, et al. (2014) Role of the TNF pathway in the progression of diabetic nephropathy in KK-A(y) mice. Am J Physiol Renal Physiol 306(11):F1335-47 |
| abstractText | Chronic inflammation promotes the progression of diabetic nephropathy (DN). However, the role of TNF-alpha remains unclear. The objectives of the present study were to examine whether TNF-alpha inhibition with a soluble TNF receptor (TNFR)2 fusion protein, i.e., etanercept (ETN), improves the early stage of DN in the type 2 diabetic model of the KK-A(y) mouse and to also investigate which TNF pathway, TNFR1 or TNFR2, is predominantly involved in the progression of this disease. ETN was injected intraperitoneally into mice for 8 wk. Renal damage was evaluated by immunohistochemistry, Western blot analysis, and/or real-time PCR. In vitro, mouse tubular proximal cells were stimulated by TNF-alpha and/or high glucose (HG) and treated with ETN. ETN dramatically improved not only albuminuria but also glycemic control. Renal mRNA and/or protein levels of TNFR2, but not TNF-alpha and TNFR1, in ETN-treated KK-A(y) mice were significantly decreased compared with untreated KK-A(y) mice. mRNA levels of ICAM-1, VCAM-1, and monocyte chemoattractant protein-1 and the number of F4/80-positive cells were all decreased after treatment. Numbers of cleaved caspase-3- and TUNEL-positive cells in untreated mice were very few and were not different from ETN-treated mice. In vitro, stimulation with TNF-alpha or HG markedly increased both mRNA levels of TNFRs, unlike in the in vivo case. Furthermore, ETN partly recovered TNF-alpha-induced but not HG-induced TNFR mRNA levels. In conclusion, it appears that ETN may improve the progression of the early stage of DN predominantly through inhibition of the anti-inflammatory action of the TNF-alpha-TNFR2 pathway. |
