Abstract
Tissue fibrosis and chronic inflammation are common causes of progressive organ damage, including progressive renal disease, leading to loss of physiological functions. Recently, it was shown that Toll-like receptor 2 (TLR2) is expressed in the kidney and activated by endogenous danger signals. The expression and function of TLR2 during renal fibrosis and chronic inflammation has however not yet been elucidated. Therefore, we studied TLR2 expression in human and murine progressive renal diseases and explored its role by inducing obstructive nephropathy in TLR2−/− or TLR2+/+ mice. We found that TLR2 is markedly upregulated on tubular and tubulointerstitial cells in patients with chronic renal injury. In mice with obstructive nephropathy, renal injury was associated with a marked upregulation and change in distribution of TLR2 and upregulation of murine TLR2 danger ligands Gp96, biglycan, and HMGB1. Notably, TLR2 enhanced inflammation as reflected by a significantly reduced influx of neutrophils and production of chemokines and TGF-β in kidneys of TLR2−/− mice compared with TLR2+/+ animals. Although, the obstructed kidneys of TLR2−/− mice had less interstitial myofibroblasts in the later phase of obstructive nephropathy, tubular injury and renal matrix accumulation was similar in both mouse strains. Together, these data demonstrate that TLR2 can initiate renal inflammation during progressive renal injury and that the absence of TLR2 does not affect the development of chronic renal injury and fibrosis.
Highlights
Tissue fibrosis is a hallmark of a variety of chronically failing organs, including progressive renal disease, and is a leading cause of morbidity and mortality worldwide [1]
We have previously shown that Toll-like receptor 2 (TLR2) plays a critical role in the initiation of acute renal inflammation and early tubular injury in a reversible model of acute renal ischemic injury [6], nothing was known about its role in chronic inflammation and fibrosis during progressive renal injury
Our results demonstrate that TLR2 and its main stress ligands are markedly upregulated in the kidney after UUOinjury, obstructive hydronephrosis (TLR2) and IgA nephropathy (TLR2) and identify TLR2 as an initiator of renal inflammation during progressive renal injury
Summary
Tissue fibrosis is a hallmark of a variety of chronically failing organs, including progressive renal disease, and is a leading cause of morbidity and mortality worldwide [1]. A growing body of evidence suggest that almost 45% of all deaths in the developed world can be ascribed to some type of chronic fibrotic disease such as interstitial pulmonary fibrosis, liver cirrhosis, and progressive renal disease [1]. The degree of inflammation and fibrosis of the tubulointerstitial compartment are strong predictive factors for the loss of renal function and the risk for progression to end-stage renal disease [2]. Irrespective of the nature of the primary disease and the originating renal compartment, renal fibrosis is considered to be the common final pathway by which kidney diseases with variable etiology progresses to end-stage renal failure. It is important to identify factors that participate in the initiation of tubulointerstitial inflammation and subsequent interstitial fibrosis during progressive renal injury. From our own and other data, it has become clear that Toll-like receptor (TLR) and 4 plays a crucial role in the induction of acute inflammation and early tubular injury in the kidney in a reversible model of acute renal injury [6,7,8]
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