C-Reactive Protein Promotes Diabetic Kidney Disease in db/db Mice via the CD32b-Smad3-mTOR signaling Pathway
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AbstractC-reactive protein (CRP) is associated with progressive diabetic nephropathy in patients with type-2 diabetes (T2DN). However, role of CRP in T2DN remains unclear. We report here that CRP is pathogenic in T2DN in db/db mice that express human CRP (CRPtg-db/db). Compared to the littermate db/db mice, CRPtg-db/db developed more severe T2DN, showing higher levels of fasting blood glucose and microalbuminuria and more progressive renal inflammation and fibrosis. Enhanced T2DN in CRPtg-db/db mice were associated with over-activation of CRP-CD32b, NF-kappa B, TGF-beta/Smad3, and mTOR signaling. Further studies in vitro defined that CRP activated Smad3 directly at 15 mins via the CD32b-ERK/p38 MAP kinase crosstalk pathway and indirectly at 24 hours through a TGF-beta 1-dependent mechanism. Importantly, CRP also activated mTOR signaling at 30 mins via a Smad3-dependent mechanism as Smad3 bound mTOR physically and CRP-induced mTOR signaling was abolished by a neutralizing CD32b antibody and a specific Smad3 inhibitor. Finally, we also found that CRP induced renal fibrosis through a CD32b-Smad3-mTOR pathway because blocking mTOR signaling with rapamycin inhibited CRP-induced CTGF and collagen I expression. Thus, CRP is pathogenic in T2DN. CRP may promote CD32b-NF-kappa B signaling to mediate renal inflammation; whereas, CRP may enhance renal fibrosis in T2DN via CD32b-Smad3-mTOR signaling.
All Author(s) ListYou YK, Huang XR, Chen HY, Lyu XF, Liu HF, Lan HY
Journal nameScientific Reports
Year2016
Month5
Day25
Volume Number6
PublisherNATURE PUBLISHING GROUP
ISSN2045-2322
eISSN2045-2322
LanguagesEnglish-United Kingdom
Web of Science Subject CategoriesMultidisciplinary Sciences; Science & Technology - Other Topics

Last updated on 2021-20-01 at 01:50