title: C-Reactive Protein Promotes Diabetic Kidney Disease in db/db Mice via the CD32b-Smad3-mTOR signaling Pathway.
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.
authors.affiliation: Institute of Nephrology, Guangdong Medical College, Zhanjiang, Guangdong, China.|Department of Medicine and Therapeutics, and Li Ka Shing Institute of Health Sciences, and Shenzhen Research Institute, the Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Yong-Ke
authors.initials: YK
authors.lastname: You
authors.affiliation: Department of Medicine and Therapeutics, and Li Ka Shing Institute of Health Sciences, and Shenzhen Research Institute, the Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Xiao-Ru
authors.initials: XR
authors.lastname: Huang
authors.affiliation: Department of Medicine and Therapeutics, and Li Ka Shing Institute of Health Sciences, and Shenzhen Research Institute, the Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Hai-Yong
authors.initials: HY
authors.lastname: Chen
authors.affiliation: Department of Medicine and Therapeutics, and Li Ka Shing Institute of Health Sciences, and Shenzhen Research Institute, the Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Xia-Fei
authors.initials: XF
authors.lastname: Lyu
authors.affiliation: Institute of Nephrology, Guangdong Medical College, Zhanjiang, Guangdong, China.
authors.forename: Hua-Feng
authors.initials: HF
authors.lastname: Liu
authors.affiliation: Department of Medicine and Therapeutics, and Li Ka Shing Institute of Health Sciences, and Shenzhen Research Institute, the Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Hui Y
authors.initials: HY
authors.lastname: Lan
mesh_terms: D000818:Animals; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C080571:Fc gamma receptor IIB; D017452:Receptors, IgG; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D002097:C-Reactive Protein; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases