Tumor Necrosis Factor and Interferon-γ Down-regulate Klotho in Mice With Colitis

Abstract

Background & Aims Klotho deficiency in hypomorphic KL mice leads to premature senescence and phenotype consistent with impaired mineral homeostasis. Klotho has anti-inflammatory properties protecting from NO-induced endothelial dysfunction, reduces the expression of endothelial adhesion molecules, and may contribute to T-cell dysfunction. Since defective Ca2+/Pi homeostasis leading to osteopenia/osteoporosis is frequently associated with human IBD, we investigated the changes in Klotho gene expression as a consequence of experimental colitis. Methods We utilized three murine IBD models: TNBS colitis, microflora-induced colitis in gnotobiotic IL-10−/− mice, and adoptive CD4+CD45RBhigh T-cell transfer colitis. These studies were followed by in vitro approaches using renal epithelial cells (mpkDCT4 and mIMCD3), and the cloned murine KL gene promoter. Results Renal expression of Klotho mRNA and protein was significantly inhibited in all three models of human IBD. This degree of inhibition was correlated with the severity of colitis, and was reversed by neutralizing anti-TNF antibodies. In vitro, TNF resulted in a significant inhibition of KL expression and was further potentiated by IFN-γ. TNF/IFN-γ combination resulted in increased iNOS expression and significantly elevated the concentration of NO in medium. The effect of IFN-γ could be reproduced by cell exposure to SNAP (NO donor), and reversed by iNOS inhibitor, L-NIL. The cytokine effects were transcriptionally mediated since Klotho mRNA stability remained unaffected, while reporter constructs with the mKL gene promoter displayed significant downregulation in transiently transfected renal epithelial cells. Conclusions These novel findings could help explain several extraintestinal complications including abnormalities in bone homeostasis in patients with chronic colitis.

Klotho Reduction in Alveolar Macrophages Contributes to Cigarette Smoke Extract-induced Inflammation in Chronic Obstructive Pulmonary Disease

“…We demonstrated that the protein expression and release level of Klotho were significantly decreased in MH-S cells treated with CSE in a time-and concentration-dependent manner. This notion is consistent with a previous study; Klotho is down-regulated by inflammatory cytokines such as TWEAK or TNF-␣ that decreased klotho gene transcription in renal tubular cells (22,23). Klotho is an important protein involved in the regulation of proinflammatory cytokine release, stress resistance, metabolism, senescence, and aging (24 -27), all of which are linked to the pathogenesis of COPD (5,6,13,29,38).…”

Factors Those Up Regulate <i>Klotho</i> and Glutathione Peroxidase-1 Gene Expression Improve Renal Function in Rats with Acute Renal Failure

“…In addition Sugiura et al (2005) reported that the renal klotho mRNA and protein expressions were significantly reduced in the rats with renal failure assessed by real-time PCR or western blotting. These results came in accordance with the recorded data of Hu et al (2010) and Thurston et al (2010) were found that klotho down-regulation occurs before changes in other markers of kidney damage. It takes place only 3 h post-ARF may be due to activation and induction of nitric oxide production.…”

Klotho to Treat Kidney Fibrosis

“…In this regard, systemic delivery of TWEAK (TNF-like weak inducer of apoptosis) or angiotensin II decreases levels of kidney Klotho, and targeting of TWEAK, TNF, or the renin-angiotensin system prevents kidney Klotho downregulation in animal models of kidney injury or systemic inflammation. 3,8,9 Similar functional studies should define the relative in vivo contribution of TGF-b1 to the regulation of kidney Klotho levels. Currently available data support a model where multiple tubular cell stressors decrease Klotho synthesis.…”

“…For some study participants, the reduction in GFR was rather modest. The inclusion criteria required the estimated GFR (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration study equation 9 to be ,90 ml/min per 1.73 m 2 . Other inclusion criteria were that the patient was not receiving chronic renal replacement treatment at the time of the physical performance assessment, did not have a stroke, was not using a wheel chair, and had completed at least one physical performance measurement.…”