Latent Transforming Growth Factor-Β1 Protects Against Diabetic Kidney Injury In A Type 1 Diabetes Mouse Model

Abstract

Introduction: Diabetic kidney disease (DKD) develops in approximately 40% of patients who are diabetic and results in heavy economic burdens. In the present study, we hypothesized that latent TGF-b1 is able to protect against fibrosis and inflammation in diabetic kidney via latent TGF-b/Arkadia/Smad7 pathways. Methods: Type 1 diabetes was induced in keratin-5 promoter-driven TGF-b transgenic (Tg) mice with overexpression of latent TGF-b and wild-type (Wt) littermates by streptozotocin (STZ). Fasting blood glucose and urine albumin were measured every 2 weeks. Mice were sacrificed at week 16 after STZ injection. Serum and kidney tissues were collected for further analysis. The signaling mechanism was examined by culture of mesangial and tubular epithelial cells under the normal/ high glucose condition. Results: The results showed that overexpression of latent TGF-b in diabetic mice significantly protected against the decline of renal function but not affected blood glucose. Mesangial matrix expansion in glomeruli and the thickening of the glomerular basement membrane were attenuated in diabetic Tg mice as shown in PAS and Masson’s trichrome staining. The expression of fibronectin and collagen IV, the fibrotic markers, was attenuated in diabetic Tg mice compared to the Wt mice as demonstrated by real-time PCR, Western blot. The results of immunohistochemistry also demonstrated a decreased infiltration of T cells and macrophages in the glomeruli and interstitium in diabetic Tg mice compared to Wt mice, which is consistent with the lower level of RNA expression of the inflammatory cytokines, IL-1b and TNF-a in the kidney of diabetic Tg mice. The attenuation of kidney injury in the diabetic Tg mice was associated with the decreased phosphorylation of Smad3 and NF-kB P65 and enhenced Smad7 expression compared to the diabetic Wt mice. Furthermore, we found that latent TGF-b suppressed Arkadia, in turn inhibited the degradation of Smad7. Conclusions: Latent TGF-b1 protects against renal fibrosis and inflammation in diabetic kidney disease by suppression of Arkadia mediated Smad7 degradation, thereby inhibiting Smad3-mediated renal fibrosis and NF-kB/P65-driven renal inflammation.