C-Reactive Protein Promotes Diabetic Kidney Disease in db/db Mice via the CD32b-Smad3-mTOR signaling Pathway

Sci Rep. 2016 May 25;6:26740. doi: 10.1038/srep26740.

Abstract

C-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-κB, TGF-β/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-β1-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-κB signaling to mediate renal inflammation; whereas, CRP may enhance renal fibrosis in T2DN via CD32b-Smad3-mTOR signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • C-Reactive Protein / genetics
  • C-Reactive Protein / metabolism*
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetic Nephropathies / genetics
  • Diabetic Nephropathies / metabolism*
  • Male
  • Mice
  • Mice, Transgenic
  • Receptors, IgG / genetics
  • Receptors, IgG / metabolism*
  • Signal Transduction*
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Fc gamma receptor IIB
  • Receptors, IgG
  • Smad3 Protein
  • Smad3 protein, mouse
  • C-Reactive Protein
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse