Effect of Youthful Blood Environment and Its Key Factor SCF on Renal Interstitial Fibrosis in Elderly Mice

Abstract Background: youthful blood environment was shown to decelerate the aging process of kidney and to attenuate senile renal fibrosis in a young-old parabiotic animal model; in addition, we identified a stem cell factor (SCF) that is closely linked with the process. To further investigate the effect of youthful blood environment on renal interstitial fibrosis and the underlying mechanisms, we bred SCF receptor c-Kit gene loss-of-function Wps/Wps mice and established a combination mice model that was subjected to unilateral ureteral obstructive (UUO) and parabiotic surgeries.Methods: Parabiotic mice were divided into isochronic parabiotic (young-young, Y-IP and old-old, O-IP) and heterochronic parabiotic (young-old, HP) groups. UUO surgery was performed in one of the parabiotic pairs in the IP group (Y-IPuuo and O-IPuuo) and in the elderly mice in the HP group (O-HPuuo). In order to study the role of SCF/c-kit on renal interstitial fibrosis, UUO surgery was performed in wildtype (WT) and Wps/Wps mice. Results: Fourteen days after UUO surgery, the kidney interstitial fibrosis area, kidney function, and the expressions of SCF/c-Kit, pNF-κB, and fibrosis-related proteins in the O-HPuuo group were significantly lower than those in the Ouuo and O-IPuuo groups. Compared with wildtype UUO mice, the expressions of pNF-κB and fibrosis-related proteins, kidney interstitial fibrosis area, and the kidney function were all significantly decreased in Wps/Wps UUO mice.Conclusions: Youthful blood environment downregulated the expressions of SCF/c-Kit in elderly UUO mice, and ameliorated UUO-induced kidney fibrosis and function loss, which may be mediated via the NF-κB pathway.

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Induction of AMPK activity corrects early pathophysiological alterations in the subtotal nephrectomy model of chronic kidney disease

AJP Renal Physiology ◽

10.1152/ajprenal.00293.2013 ◽

2013 ◽

Vol 305 (5) ◽

pp. F727-F733 ◽

Cited By ~ 38

Author(s):

Joseph Satriano ◽

Kumar Sharma ◽

Roland C. Blantz ◽

Aihua Deng

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Kidney Function ◽

Rat Kidney ◽

Metabolic Efficiency ◽

Loss Of Function ◽

Kidney Fibrosis ◽

Subtotal Nephrectomy ◽

Progression Of Disease ◽

Ampk Activity

The rat kidney ablation and infarction (A/I) model of subtotal or 5/6th nephrectomy is the most commonly studied model of nondiabetic chronic kidney disease (CKD). The A/I kidney at 1 wk exhibits reductions in kidney function, as determined by glomerular filtration rate, and diminished metabolic efficiency as determined by oxygen consumption per sodium transport (QO2/TNa). As renoprotective AMPK activity is affected by metabolic changes and cellular stress, we evaluated AMPK activity in this model system. We show that these early pathophysiological changes are accompanied by a paradoxical decrease in AMPK activity. Over time, these kidney parameters progressively worsen with extensive kidney structural, functional, metabolic, and fibrotic changes observed at 4 wk after A/I. We show that induction of AMPK activity with either metformin or 5-aminoimidazole-4-carboxamide ribonucleotide increases AMPK activity in this model and also corrects kidney metabolic inefficiency, improves kidney function, and ameliorates kidney fibrosis and structural alterations. We conclude that AMPK activity is reduced in the subtotal nephrectomy model of nondiabetic CKD, that altered regulation of AMPK is coincident with the progression of disease parameters, and that restoration of AMPK activity can suppress the progressive loss of function characteristic of this model. We propose that induction of AMPK activity may prove an effective therapeutic target for the treatment of nondiabetic CKD.

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Selective Wnt/β-Catenin Pathway Activation Concomitant With Sustained Overexpression of miR-21 is Responsible for Aristolochic Acid-Induced AKI-to-CKD Transition

Frontiers in Pharmacology ◽

10.3389/fphar.2021.667282 ◽

2021 ◽

Vol 12 ◽

Author(s):

Qing Kuang ◽

Sheng Wu ◽

Ning Xue ◽

Xiaoyan Wang ◽

Xiaoqianq Ding ◽

...

Keyword(s):

Aristolochic Acid ◽

Interstitial Fibrosis ◽

Cumulative Risk ◽

Kidney Injury ◽

Renal Tissue ◽

Ckd Progression ◽

Renal Interstitial Fibrosis ◽

Underlying Mechanisms ◽

Induced Apoptosis ◽

Apoptosis And Inflammation

Acute kidney injury (AKI) is increasingly recognized as a cumulative risk factor for chronic kidney disease (CKD) progression. However, the underlying mechanisms remain unclear. Using an aristolochic acid (AA)-induced mouse model of AKI-to-CKD transition, we found that the development of tubulointerstitial fibrosis following AKI was accompanied with a strong activation of miR-21 and canonical Wnt signaling, whereas inhibition of miR-21 or selective silencing of Wnt ligands partially attenuated AKI-to-CKD transition. To explore the interaction between miR-21 and Wnt/β-catenin signaling, we examined the effects of genetic absence or pharmacologic inhibition of miR-21 on Wnt/β-catenin pathway expression. In miR-21−/− mice and in wild-type mice treated with anti-miR21 oligos, Wnt1 and Wnt4 canonical signaling in the renal tissue was significantly reduced, with partial reversal of renal interstitial fibrosis. Although the renal abundance of miR-21 remained unchanged after inhibition or activation of Wnt/β-catenin signaling, early intervention with ICG-001, a β-catenin inhibitor, significantly attenuated renal interstitial fibrosis. Moreover, early (within 24 h), but not late β-catenin inhibition after AA administration attenuated AA-induced apoptosis and inflammation. In conclusion, inhibition of miR-21 or β-catenin signaling may be an effective approach to prevent AKI-to-CKD progression.

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Macrophage Overexpressing NGAL Ameliorated Kidney Fibrosis in the UUO Mice Model

Cellular Physiology and Biochemistry ◽

10.1159/000479835 ◽

2017 ◽

Vol 42 (5) ◽

pp. 1945-1960 ◽

Cited By ~ 19

Author(s):

Roser Guiteras ◽

Anna Sola ◽

Maria Flaquer ◽

Georgina Hotter ◽

Joan Torras ◽

...

Keyword(s):

Cell Tracking ◽

Interstitial Fibrosis ◽

Lipocalin 2 ◽

Mice Model ◽

Kidney Fibrosis ◽

Alternatively Activated Macrophages ◽

Neutrophil Gelatinase Associated Lipocalin ◽

And Function ◽

Therapy Success

Background/Aims: Alternatively activated macrophages (AAM) have regenerative and anti-inflammatory characteristics. Here, we sought to evaluate whether AAM cell therapy reduces renal inflammation and fibrosis in the unilateral ureteral obstruction (UUO) mice model. Methods: We stabilized macrophages by adenoviral vector NGAL (Neutrophil gelatinase-associated lipocalin-2) and infused them into UUO mice. To ascertain whether macrophages were capable of reaching the obstructed kidney, macrophages were stained and detected by in vivo cell tracking. Results: We demonstrated that some infused macrophages reached the obstructed kidney and that infusion of macrophages overexpressing NGAL was associated with reduced kidney interstitial fibrosis and inflammation. This therapeutic effect was mainly associated with the phenotype and function preservation of the transferred macrophages isolated from the obstructed kidney Conclusions: Macrophage plasticity is a major hurdle for achieving macrophage therapy success in chronic nephropathies and could be overcome by transferring lipocalin-2.

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Inhibition of CTCF-regulated miRNA-185-5p mitigates renal interstitial fibrosis of chronic kidney disease

Epigenomics ◽

10.2217/epi-2020-0243 ◽

2021 ◽

Author(s):

Jiajun Zhou ◽

Han Zhou ◽

Yong Liu ◽

Caixin Liu

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Mouse Model ◽

Ureteral Obstruction ◽

Interstitial Fibrosis ◽

Unilateral Ureteral Obstruction ◽

Renal Interstitial Fibrosis ◽

Underlying Mechanisms

Aim: The present study aimed to elucidate the effect of CTCF on renal interstitial fibrosis in chronic kidney disease (CKD) and underlying mechanisms. Materials & methods: We measured NPHS2 expression and investigated its function in a unilateral ureteral obstruction-induced mouse model of CKD. Results: NPHS2 was poorly expressed in CKD mice. miR-185-5p targeted NPHS2 and reduced its expression, leading to increased α-SMA and COL I/III expression, increased renal interstitial fibrosis area and elevated phosphorylated vasodilator-stimulated phosphoprotein/vasodilator-stimulated phosphoprotein ratio. Cotreatment with CTCF downregulated miR-185-5p expression and abolished its effects in the CKD model. Conclusion: CTCF suppressed miR-185-5p and upregulated its target NPHS2, with a net effect of alleviating renal interstitial fibrosis in CKD.

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