MO235: TGF-Β1/PSMAD3 Dependent Signaling in Glomerulonephritis and Its Association With Renal Injury and Progression

Abstract BACKGROUND AND AIMS Transforming growth factor-β1 (TGF-β1) has long been considered as a potent, multifunctional cytokine that is involved in the pathogenesis of fibrosis and inflammation, which acts through Smad signaling in renal pathology. We intended to investigate the expression of TGF-β1/Smad3 signaling in glomerulonephritis (GN) and to assess its role as risk factor for progression to chronic kidney disease (CKD). METHOD We evaluated the immunohistochemical expression of TGF-β1, phosphorylated Smad3 (pSmad3) and Smad7 semiquantitatively and quantitatively using computerized image analysis program in different compartments of 50 renal biopsies with GN and the results were statistically analyzed with clinicopathological parameters. We also examined the associations among their expressions, the impact of their co-expression and their role in progression to CKD. RESULTS TGF-β1 expression correlated positively with segmental glomerulosclerosis (P = .025) and creatinine level at diagnosis (p = .002), while pSmad3 expression with interstitial inflammation (P = .024). In glomerulus, we recorded different expression patterns of pSmad3 in crescents, while concomitant expressions of strong Smad7 and moderate pSmad3 were observed to be correlated with renal inflammation, such as cellular crescent (P = .011), intense interstitial inflammation (P = .029) and lower serum complement 3 (P = .028) and complement 4 (P = .029). We also reported a significant preferable expression between pSmad3 and glomerular endothelial cells of proliferative GN (P = .045) and podocytes of non-proliferative GN (P = .005). Finally, on multivariate Cox-regression analysis, TGF-β1 expression (HR = 5.08; 95% CI 1.133–22.78; P = .034) was emerged as independent predictor for CKD. CONCLUSION TGF-β1/Smad3 dependent signaling is upregulated, especially in proliferative GN, with specific characteristics in different forms of GN. TGF-β1 expression is indicated as independent risk factor for progression to CKD, while specific co-expression pattern of pSmad3 and Smad7 in glomerulus is correlated with renal inflammation.