Abstract
Renal fibrosis plays an important role in the onset and progression of chronic kidney diseases. Many studies have demonstrated that heme oxygenase-1 (HO-1) is involved in diverse biological processes as a cytoprotective molecule, including anti-inflammatory, anti-oxidant, anti-apoptotic, antiproliferative, and immunomodulatory effects. However, the mechanisms of HO-1 prevention in renal interstitial fibrosis remain unknown. In this study, HO-1 transgenic (TG) mice were employed to investigate the effect of HO-1 on renal fibrosis using a unilateral ureter obstruction (UUO) model and to explore the potential mechanisms. We found that HO-1 was adaptively upregulated in kidneys of both TG and wild type (WT) mice after UUO. The levels of HO-1 mRNA and protein were increased in TG mice compared with WT mice under normal conditions. HO-1 expression was further enhanced after UUO and remained high during the entire experimental process. Renal interstitial fibrosis in the TG group was significantly attenuated compared with that in the WT group after UUO. Moreover, overexpression of HO-1 inhibited the loss of peritubular capillaries. In addition, UUO-induced activation and proliferation of myofibroblasts were suppressed by HO-1 overexpression. Furthermore, HO-1 restrained tubulointerstitial infiltration of macrophages and regulated the secretion of inflammatory cytokines in UUO mice. We also found that high expression of HO-1 inhibited reactivation of Wnt/β-catenin signaling, which could play a crucial role in attenuating renal fibrosis. In conclusion, these data suggest that HO-1 prevents renal tubulointerstitial fibrosis possibly by regulating the inflammatory response and Wnt/β-catenin signaling. This study provides evidence that augmentation of HO-1 levels may be a therapeutic strategy against renal interstitial fibrosis.
Highlights
Progressive renal tubulointerstitial fibrosis is a common pathway leading to end-stage renal diseases.[1,2,3] Tubulointerstitial fibrosis is characterized by the destruction of renal tubules, infiltration of inflammatory cells, rarefaction of the peritubular microvasculature, accumulation of myofibroblasts, and excessive deposition of extracellular matrix (ECM), which are regulated by many signaling pathways and thought to play pivotal roles in the pathogenesis of chronic kidney diseases (CKDs).[1,2,3] it is important to prevent renal interstitial fibrosis to slow the progression of CKD
The expression of kidney Heme oxygenase-1 (HO-1) mRNA was detected. It obviously increased in the TG group compared with the wild type (WT) group, especially after ureter obstruction (UUO) injury, and remained high throughout the entire experimental process (Fig 1A)
Increased HO-1 expression was observed in tubules and interstitium after UUO injury in WT mice (Fig 1B)
Summary
Progressive renal tubulointerstitial fibrosis is a common pathway leading to end-stage renal diseases.[1,2,3] Tubulointerstitial fibrosis is characterized by the destruction of renal tubules, infiltration of inflammatory cells, rarefaction of the peritubular microvasculature, accumulation of myofibroblasts, and excessive deposition of extracellular matrix (ECM), which are regulated by many signaling pathways and thought to play pivotal roles in the pathogenesis of chronic kidney diseases (CKDs).[1,2,3] it is important to prevent renal interstitial fibrosis to slow the progression of CKD. Researchers have demonstrated that HO-1 is involved in antiinflammatory, anti-oxidant, anti-apoptotic, antiproliferative and immunomodulatory effects that protect diverse organs against injury, including acute kidney injury (AKI).[4] even though the salutary effects of HO-1 during short-term renal stress have been established, it is not clear whether such a paradigm can be extended to chronic renal fibrosis. Previous studies reported that HO-1 was upregulated in tubular epithelial cells of the human kidney in various renal diseases, epithelia are more susceptible to oxidative stress due to the lack of this critical enzyme,[5] and HO-1 deficiency promotes epithelial-mesenchymal transition and renal fibrosis. [6] whether overexpression of HO-1 is beneficial or detrimental in kidney disease is unclear. Induction of HO-1 halts renal interstitial fibrosis, [8] the potential mechanisms remain unclear
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