Renal upregulation of HO-1 reduces albumin-driven MCP-1 production: implications for chronic kidney disease

2007 ◽  
Vol 292 (2) ◽  
pp. F837-F844 ◽  
Author(s):  
Narayana S. Murali ◽  
Allan W. Ackerman ◽  
Anthony J. Croatt ◽  
Jingfei Cheng ◽  
Joseph P. Grande ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Proximal Tubule ◽  
Heme Oxygenase 1 ◽  
Inhibitory Effects ◽  
Monocyte Chemoattractant Protein 1 ◽  
Renal Tubular ◽  
A Site ◽  
Erk Activity ◽  
Dependent Pathway

Proteinuria contributes to chronic kidney disease by stimulating renal tubular epithelial cells to produce cytokines such as monocyte chemoattractant protein-1 (MCP-1). The present study determined whether cellular overexpression of heme oxygenase-1 (HO-1) can influence albumin-stimulated MCP-1 production. In response to bovine serum albumin, NRK-52E cells constitutively overexpressing HO-1 (HO-1 OE cells) exhibit less induction of MCP-1 mRNA and less production of MCP-1 protein compared with similarly treated, control NRK-52E cells (CON cells). In wild-type NRK-52E cells, and under these conditions, we demonstrate that the induction of MCP-1 is critically dependent on intact NF-κB binding sites in the MCP-1 promoter. In response to albumin, CON cells exhibit activation of NF-κB, and this is reduced in HO-1 OE cells. Albumin also activates ERK1/2 and increases ERK activity, both of which are exaggerated in HO-1 OE cells. Studies with an inhibitor of MAPK/ERK kinase (U0126) demonstrate that the inhibitory effects of U0126 on MCP-1 production are attenuated in HO-1 OE cells. We conclude that HO-1 overexpression in the proximal tubule reduces MCP-1 production in response to albumin, and this occurs, at least in part, by inhibiting an ERK-dependent, NF-κB-dependent pathway at a site that is distal to the activation of ERK. These findings suggest that the induction of HO-1 in the proximal tubule, as occurs in chronic kidney disease, may be a countervailing response that reduces albumin-stimulated production of cytokines such as MCP-1.

scholarly journals Permissive effect of GSK3β on profibrogenic plasticity of renal tubular cells in progressive chronic kidney disease

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Bohan Chen ◽  
Pei Wang ◽  
Xianhui Liang ◽  
Chunming Jiang ◽  
Yan Ge ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Binding Protein ◽  
Renal Tubules ◽  
Genetic Ablation ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Renal Fibrogenesis ◽  
Tgf Β1

AbstractRenal tubular epithelial cells (TECs) play a key role in renal fibrogenesis. After persistent injuries that are beyond self-healing capacity, TECs will dedifferentiate, undergo growth arrest, convert to profibrogenic phenotypes, and resort to maladaptive plasticity that ultimately results in renal fibrosis. Evidence suggests that glycogen synthase kinase (GSK) 3β is centrally implicated in kidney injury. However, its role in renal fibrogenesis is obscure. Analysis of publicly available kidney transcriptome database demonstrated that patients with progressive chronic kidney disease (CKD) exhibited GSK3β overexpression in renal tubulointerstitium, in which the predefined hallmark gene sets implicated in fibrogenesis were remarkably enriched. In vitro, TGF-β1 treatment augmented GSK3β expression in TECs, concomitant with dedifferentiation, cell cycle arrest at G2/M phase, excessive accumulation of extracellular matrix, and overproduction of profibrotic cytokines like PAI-1 and CTGF. All these profibrogenic phenotypes were largely abrogated by GSK3β inhibitors or by ectopic expression of a dominant-negative mutant of GSK3β but reinforced in cells expressing the constitutively active mutant of GSK3β. Mechanistically, GSK3β suppressed, whereas inhibiting GSK3β facilitated, the activity of cAMP response element-binding protein (CREB), which competes for CREB-binding protein, a transcriptional coactivator essential for TGF-β1/Smad signaling pathway to drive TECs profibrogenic plasticity. In vivo, in mice with folic acid-induced progressive CKD, targeting of GSK3β in renal tubules via genetic ablation or by microdose lithium mitigated the profibrogenic plasticity of TEC, concomitant with attenuated interstitial fibrosis and tubular atrophy. Collectively, GSK3β is likely a pragmatic therapeutic target for averting profibrogenic plasticity of TECs and improving renal fibrosis.

scholarly journals Uremic Toxins and Frailty in Patients with Chronic Kidney Disease: A Molecular Insight

2021 ◽  
Vol 22 (12) ◽  
pp. 6270
Author(s):  
Chia-Ter Chao ◽  
Shih-Hua Lin
Keyword(s):  
Chronic Kidney Disease ◽  
Renal Function ◽  
Kidney Disease ◽  
Uremic Toxins ◽  
Heme Oxygenase 1 ◽  
Signal Pathways ◽  
Uremic Toxin ◽  
Nuclear Factor ◽  
Cognitive Frailty ◽  
Renal Function Decline

The accumulation of uremic toxins (UTs) is a prototypical manifestation of uremic milieu that follows renal function decline (chronic kidney disease, CKD). Frailty as a potential outcome-relevant indicator is also prevalent in CKD. The intertwined relationship between uremic toxins, including small/large solutes (phosphate, asymmetric dimethylarginine) and protein-bound ones like indoxyl sulfate (IS) and p-cresyl sulfate (pCS), and frailty pathogenesis has been documented recently. Uremic toxins were shown in vitro and in vivo to induce noxious effects on many organ systems and likely influenced frailty development through their effects on multiple preceding events and companions of frailty, such as sarcopenia/muscle wasting, cognitive impairment/cognitive frailty, osteoporosis/osteodystrophy, vascular calcification, and cardiopulmonary deconditioning. These organ-specific effects may be mediated through different molecular mechanisms or signal pathways such as peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), mitogen-activated protein kinase (MAPK) signaling, aryl hydrocarbon receptor (AhR)/nuclear factor-κB (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Runt-related transcription factor 2 (RUNX2), bone morphogenic protein 2 (BMP2), osterix, Notch signaling, autophagy effectors, microRNAs, and reactive oxygen species induction. Anecdotal clinical studies also suggest that frailty may further accelerate renal function decline, thereby augmenting the accumulation of UTs in affected individuals. Judging from these threads of evidence, management strategies aiming for uremic toxin reduction may be a promising approach for frailty amelioration in patients with CKD. Uremic toxin lowering strategies may bear the potential of improving patients’ outcomes and restoring their quality of life, through frailty attenuation. Pathogenic molecule-targeted therapeutics potentially disconnect the association between uremic toxins and frailty, additionally serving as an outcome-modifying approach in the future.

scholarly journals A new model of an arteriovenous fistula in chronic kidney disease in the mouse: beneficial effects of upregulated heme oxygenase-1

2016 ◽  
Vol 310 (6) ◽  
pp. F466-F476 ◽  
Author(s):  
Lu Kang ◽  
Joseph P. Grande ◽  
Matthew L. Hillestad ◽  
Anthony J. Croatt ◽  
Michael A. Barry ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Blood Flow ◽  
Kidney Disease ◽  
Arteriovenous Fistula ◽  
Heme Oxygenase ◽  
Viral Gene ◽  
Heme Oxygenase 1 ◽  
Beneficial Effects ◽  
Viral Gene Delivery ◽  
Venous Wall

The arteriovenous fistula (AVF) is the preferred hemodialysis vascular access, but it is complicated by high failure rates and attendant morbidity. This study provides the first description of a murine AVF model that recapitulates two salient features of hemodialysis AVFs, namely, anastomosis of end-vein to side-artery to create the AVF and the presence of chronic kidney disease (CKD). CKD reduced AVF blood flow, observed as early as 3 days after AVF creation, and increased neointimal hyperplasia, venous wall thickness, thrombus formation, and vasculopathic gene expression in the AVF. These adverse effects of CKD could not be ascribed to preexisting alterations in blood pressure or vascular reactivity in this CKD model. In addition to vasculopathic genes, CKD induced potentially vasoprotective genes in the AVF such as heme oxygenase-1 (HO-1) and HO-2. To determine whether prior HO-1 upregulation may protect in this model, we upregulated HO-1 by adeno-associated viral gene delivery, achieving marked venous induction of the HO-1 protein and HO activity. Such HO-1 upregulation improved AVF blood flow and decreased venous wall thickness in the AVF. Finally, we demonstrate that the administration of carbon monoxide, a product of HO, acutely increased AVF blood flow. This study thus demonstrates: 1) the feasibility of a clinically relevant murine AVF model created in the presence of CKD and involving an end-vein to side-artery anastomosis; 2) the exacerbatory effect of CKD on clinically relevant features of this model; and 3) the beneficial effects in this model conferred by HO-1 upregulation by adeno-associated viral gene delivery.

The Efficacy of Adipose-Derived Stem Cells (ADSCs) on Chronic Kidney Disease in Dogs

2019 ◽  
Vol 11 (12) ◽  
pp. 1724-1728
Author(s):  
Mengling Zhu ◽  
Xiaoyun Lai ◽  
Yixin Wen ◽  
Haibin Zhang
Keyword(s):  
Chronic Kidney Disease ◽  
Renal Function ◽  
Treatment Group ◽  
Kidney Disease ◽  
Adipose Derived Stem Cells ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Urine Protein ◽  
Treatment Groups ◽  
Renal Tubular

To investigate the therapeutic effect of adipose-derived stem cells (ADSCs) on chronic kidney disease (CKD) in dogs, blood routine examination, urine protein quantitative test, renal function test, urine sediment staining microscopy and B-ultrasonic test of kidney were used to compare the treatment of chronic kidney disease in dogs treated with three different therapies (NT treatment group: traditional supportive therapy group; MT1 treatment group: ADSCs treatment group; MT2 treatment group: NT mixed MT1 treatment group). Results showed that the numbers of red blood cells (RBC), hemoglobin (HGB) and hematocrit (HCT) in MT1 and MT2 treatment groups were higher than those in the NT group, and the urine protein excretion and the levels of serum urea and creatinine in MT1 and MT2 treatment groups were lower than those in the NT treatment group. Besides, there was no further deterioration of kidney morphology in MT1 and MT2 treatment groups. However, a large number of renal tubular epithelial cells and epithelial casts were observed in NT treatment group, while only a small number of renal tubular epithelial cells were observed in MT1 and MT2 treatment groups, indicating the intravenous injection of ADSCs can significantly improve the physical signs and renal function of dogs with CKD, and combined with the traditional therapy, ADSCs has a good prospect for the treatment of CKD in dogs.

Reduced urinary corin levels in patients with chronic kidney disease

2013 ◽  
Vol 124 (12) ◽  
pp. 709-717 ◽  
Author(s):  
Chaodong Fang ◽  
Lei Shen ◽  
Liang Dong ◽  
Meng Liu ◽  
Sensen Shi ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Human Urine ◽  
Animal Studies ◽  
Kidney Tissue ◽  
Renal Tubules ◽  
Tissue Samples ◽  
Protein Levels ◽  
Normal Individuals ◽  
Renal Tubular

Corin is a cardiac protease that regulates BP (blood pressure) by activating natriuretic peptides. Recent animal studies identified corin expression in the kidney where it may regulate renal function. In the present study, we tested the hypothesis that corin may be present in human urine and that urinary corin levels may be altered in patients with kidney disease. We obtained urine and kidney tissue samples from normal individuals and CKD (chronic kidney disease) patients. Using ELISA, we detected corin protein in human urine. In normal individuals, urinary corin levels did not correlate with that of plasma, indicating that urinary corin is probably of kidney origin. Compared with normal controls, CKD patients had markedly reduced urinary corin levels and this reduction correlated with disease severity. By immunostaining, human corin protein was identified on the epithelial cell surface in renal tubules. The renal corin mRNA and protein levels were significantly lower in CKD patients than non-CKD controls. The results indicate that renal tubular corin may be shed into urine and that urinary and renal corin levels were reduced in CKD patients. These data suggest that reduced corin levels in the kidney may reflect the underlying pathology in CKD.

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