Deletion of Smad3 protects against C-reactive protein-induced renal fibrosis and inflammation in obstructive nephropathy

Abstract

Introduction and Aims: Elevated plasma levels of C-reactive protein (CRP) are closely associated with progressive renal injury in patients with chronic kidney disease (CKD). Here, we tested a hypothesis that CRP may promote renal fibrosis and inflammation via a TGF-β/Smad3-dependent mechanism.Methods: Role and mechanisms of TGF-β/Smad3 in CRP-induced renal fibrosis and inflammation were examined in a mouse model of unilateral ureteral obstruction (UUO) induced in CRP Tg/Smad3 KO mice and in a rat tubular epithelial cell line in which Smad3 gene is stably knocked down (S3KD-NRK52E). Results: We found that mice overexpressing the human CRP gene were largely promoted renal inflammation and fibrosis as evidenced by increasing IL-1β, TNF-α, MCP-1 expression, F4/80 + macrophages infiltration, and marked accumulation of α-smooth muscle actin (α-SMA), collagen I and fibronectin in the UUO kidney, which were blunted when Smad3 gene was deleted in CRPtg-Smad3KO. Mechanistically, we found that the protection of renal inflammation and fibrosis in the UUO kidney of CRPtg-Smad3KO mice was associated with the inactivation of CD32-NF-κB and TGF-β/Smad3 signaling. Conclusion:In conclusion, Smad3 deficiency protects against CRP-mediated renal inflammation and fibrosis in the UUO kidney by inactivating CD32-NF-κB and TGF-β/Smad3 signaling.

Smad3 Signatures in Renal Inflammation and Fibrosis

“…CRP can activate Smad3 to mediate renal fibrosis directly via the CD32b-ERK/p38 MAP kinase-crosstalk pathway and indirectly through the TGF-β1-dependent mechanism 41 . This is also confirmed by deleting Smad3 to inhibit UUO-induced renal fibrosis in CRP transgenic mice 43 .…”

“…Interestingly, recent studies also show that deletion of Smad3 from db/db and human CRP transgenic mice can inhibit renal inflammation by blocking MCP-1-dependent macrophage infiltration 65 . Furthermore, deficiency of Smad3 shows to exert its inhibitory effect on NF-κB-driven renal inflammation as seen in many mouse models of kidney disorders 41 , 43 . It is likely that deletion of Smad3 may suppress expression of E3 ubiquitin-protein ligases such as Smurf1/Smurf2 that target Smad2, Smad7, and TβRI for degradation.…”

Nontoxic Concentration of Ochratoxin A Aggravates Renal Fibrosis Induced by Adriamycin/Cyclosporine A Nephropathy via TGF-β1/SMAD2/3

“…Treatment with specific inhibitors SIS3 and SB431542 also demonstrated that SMAD3 and SMAD2 were jointly involved in the nontoxic concentration of OTA exacerbating ADR- or CSA-induced glomerular injury or glomerular cytotoxicity. Consistent with our study, inhibition of TGF-β1 signaling limited the progression of fibrosis in a variety of renal disease models. − Therefore, inhibition of TGF-β1/SMAD signaling can alleviate CKD, suggesting that the TGF-β1/SMAD2/3 signaling pathway will be a potential target for future research on prevention and treatment of OTA poisoning and the development of CKD.…”

The System Profile of Renal Drug Transporters in Tubulointerstitial Fibrosis Model and Consequent Effect on Pharmacokinetics

“…Five different cortical fields were randomly selected from each slice (magnification 200 times). The area of fibrotic lesions was expressed as the percentage of fibrotic area in the whole cortex [ 37 , 38 ].…”