Progression of diabetic nephropathy and adverse renal outcomes: possible involvement of Toll-like receptor 4 expression

Background Diabetic nephropathy (DN) remains a leading cause of end-stage kidney disease despite current therapies. Experimental data implicate Toll-like receptor 4 (TLR4) in DN pathogenesis; however, human evidence, particularly on histological severity and long-term outcomes, is limited. We hypothesized that renal TLR4 expression is correlated with tissue injury and adverse prognosis in DN. Methods In 146 adults with biopsy-confirmed DN, we evaluated TLR4 expression in the glomeruli and proximal tubules using immunohistochemical staining. Histological injuries were scored according to the Renal Pathology Society classification. TLR4 expression was graded in the proximal tubular and glomerular epithelial cells. We subsequently investigated whether TLR4 expression is associated with kidney histological damage and whether it relates to renal prognosis. Results There was a significant difference in the severity of glomerular lesions across different levels of glomerular epithelial TLR4 expression. Additionally, the extent of interstitial fibrosis and tubular atrophy (IFTA) and interstitial inflammation significantly differed across different levels of proximal tubular TLR4 expression. Overall, TLR4 status did not predict kidney failure-free survival; however, among patients with IFTA < 50% (n = 63), moderate-to-severe tubular TLR4 expression was associated with worse survival than negative-to-mild expression ( p = 0.021). In the low-IFTA subgroup, there were significant differences in systolic blood pressure, proteinuria, and total cholesterol levels across the levels of tubular TLR4 expression. Conclusion These findings indicate possible involvement of TLR4 expression in histological injury and poor renal prognosis in DN, especially before the development of extensive fibrosis. TLR4 and its endogenous ligands are potential novel therapeutic targets for DN.