Role of inflammation in túbulo-interstitial damage associated to obstructive nephropathy

Abstract

Obstructive nephropathy is characterized by an inflammatory state in the kidney, that is promoted by cytokines and growth factors produced by damaged tubular cells, infiltrated macrophages and accumulated myofibroblasts. This inflammatory state contributes to tubular atrophy and interstitial fibrosis characteristic of obstructive nephropathy. Accumulation of leukocytes, especially macrophages and T lymphocytes, in the renal interstitium is strongly associated to the progression of renal injury. Proinflammatory cytokines, NF-kappaB activation, adhesion molecules, chemokines, growth factors, NO and oxidative stress contribute in different ways to progressive renal damage induced by obstructive nephropathy, as they induce leukocytes recruitment, tubular cell apoptosis and interstitial fibrosis. Increased angiotensin II production, increased oxidative stress and high levels of proinflammatory cytokines contribute to NF-kappaB activation which in turn induce the expression of adhesion molecules and chemokines responsible for leukocyte recruitment and iNOS and cytokines overexpression, which aggravates the inflammatory response in the damaged kidney. In this manuscript we revise the different events and regulatory mechanisms involved in inflammation associated to obstructive nephropathy.

Figure 1

Schematic representation of some of the signaling intermediates potentially involved in regulation of inflammatory response after UUO. UUO induces IL-1β and TNF-α expression, leading to NF-κB activation. UUO also induces both oxidative stress and increased Angiotensin II (Ang II) levels. Ang II also activate the transcription factor NF-κB, both directly and indirectly, by promoting oxidative stress, which in turns activate Ang II by regulating angiotensinogen expression. TGF-β activates NF-κB through I-κB inhibition, a mechanism shared by TNF-α. NF-κB activation concludes in IL-1β and TNF-α expression enhancing NF-κB activation. Also NF-κB controls the expression of genes encoding pro-inflammatory cytokines, adhesion molecules and iNOS.

Figure 2

Schematic illustration of the Osteopontin signaling pathway and effects during obstructive nephropathy. UUO induces increased Angiotensin II (Ang II) levels which up-regulated Osteopontin (OPN) expression through AT1 receptor. This effect can be inhibited by statins. UUO also increases tubular expression of the CD44, a receptor of OPN. OPN actions may be mediated by uPAR, which reduces tubular apoptosis and interstitial fibrosis through reduced plasminogen activator inhibitor-1 (PAI-1) but promotes macrophage infiltration in the obstructive nephropathy. Discontinuous arrow connecting OPN and uPAR means that, although the relationship between them has been demonstrated "in vitro" (ref. 126 and 127), no direct relationship has been demonstrated in experimental or clinical models of obstructive nephropathy.