Heterozygous mice for TGF-βIIR gene are resistant to the progression of streptozotocin-induced diabetic nephropathy

Heterozygous mice for TGF-βIIR gene are resistant to the progression of streptozotocin-induced diabetic nephropathy. Transforming growth factor-β (TGF-β) receptor complex and its downstream Smad signaling intermediates constitute an extracellular matrix (ECM) accumulation pathway. In the present study, we examined whether decreased expression of the TGF-β type II receptor (TGF-βIIR) in TGF-βIIR gene heterozygous (TGF-βIIR+/−) (HT) mice could inhibit the Smad signaling pathway and subsequent progression of renal lesions when streptozotocin (STZ) diabetes is induced. At the end of the 28-week experiment after STZ injections, wild-type diabetic mice showed severe glomerular hypertrophy and mesangial matrix accumulation occasionally featuring nodular glomerulosclerosis. In contrast, mean glomerular area and mesangial volume density were significantly decreased in the HT diabetic mice as compared with the wild-type diabetic mice. Immunostaining for phosphorylated Smad2/Smad3 and TGF-βIIR in the glomerular cells was also significantly reduced in the HT diabetic mice. Southwestern histochemistry using digoxigenin-labeled CAGA sequence probes showed that localization of labeled probes to the nuclei of glomerular cells in the HT diabetic mice was significantly less frequent than that in the wild-type diabetic animals. Northern blot analysis showed that α1(IV) collagen mRNA levels were significantly reduced in the kidney tissue of HT diabetic mice as compared with the wild-type diabetic mice. These results suggest that decreased expression of TGF-βIIR in the HT diabetic mice can inhibit the progression of diabetic renal injury by inhibiting the downstream Smad signaling pathway and subsequent ECM gene expression. Thus, TGF-βIIR appears to play an important role in the progression of diabetic nephropathy by mediating intracellular Smad signaling.