Aging, Cellular Senescence, and Kidney Fibrosis

Susnik, Nathan; Melk, Anette; Schmitt, Roland

doi:10.1007/s40139-017-0143-9

Cited by 6 publications

(4 citation statements)

References 106 publications

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“…Understanding the time course of the disease process was key to allowing optimal selection of study duration and relating this to changes in collagen levels (and thus fibrosis), while using TG2 as an exemplar molecule of clinical stage target in CKD. The model was developed in adult animals to assist with translation, as CKD is typically a disease of later life in which changes occur in multiple parameters associated with fibrosis, including cell senescence, 19,20 promoter methylation, 21 ECM homeostasis, 22 and hemodynamics. 23 Overall, these data demonstrate a clear development of tubulointerstitial fibrosis over the 3-to 6-week study period, although data from the different methods used to assess the extent of fibrosis in this study were not totally aligned.…”

Section: Discussionmentioning

confidence: 99%

Development of a unilateral ureteral obstruction model in cynomolgus monkeys

Huang

Ni²,

Duncan

et al. 2021

Anim Models and Exp Med

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Background: Chronic kidney disease (CKD) has a high global prevalence and large unmet need. Central to developing new CKD therapies are in vivo models in CKD.However, next-generation antibody, protein, and gene therapies are highly specific, meaning some do not cross-react with rodent targets. This complicates preclinical development, as established in vivo rodent models cannot be utilized unless tool therapeutics are also developed. Tool compounds can be difficult to develop and, if available, typically have different epitopes, sequences, and/or altered affinity, making it unclear how efficacious the lead therapeutic may be, or what dosing regimen to investigate. To address this, we aimed to develop a nonhuman primate model of CKD. Methods:In vivo rodent unilateral ureteral obstruction (UUO) models kidney fibrosis and is commonly used due to its rapidity, consistency, and ease. We describe translation of this model to the cynomolgus monkey, specifically optimizing the model duration to allow adequate time for assessment of novel therapeutics prior to the fibrotic plateau. Results:We demonstrated that disease developed more slowly in cynomolgus monkeys than in rodents post-UUO, with advanced fibrosis developing by 6 weeks. The tubulointerstitial fibrosis in cynomolgus monkeys was more consistent with human obstructive disease than in rodents, having a more aggressive tubular basement expansion and a higher fibroblast infiltration. The fibrosis was also associated with increased transglutaminase activity, consistent with that seen in patients with CKD. Conclusion:This cynomolgus monkey UUO model can be used to test potential human-specific therapeutics in kidney fibrosis.

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Section: Discussionmentioning

confidence: 99%

Development of a unilateral ureteral obstruction model in cynomolgus monkeys

Huang

Ni²,

Duncan

et al. 2021

Anim Models and Exp Med

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“…Repeated exposure to injuries can also lead to cellular senescence. While many of the tubular epithelial cells undergo apoptosis, some will transition into cellular senescence ( 17 ). In UUO, injuries are continuous and increasingly widespread, which increases the amount of cellular senescence (as shown in Figure 3 ) and p16 mRNA expression in the UUO groups compared with those in the SO group.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of p16, Bax and Bcl-2 mRNAExpression Associated with Epithelial Apoptosis and Myofibroblast Proliferation in Kidney Fibrosis Model in Mice

Sulistiyowati

Yunus

Sari

et al. 2020

MJMS

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Background Cellular senescence may play a role in the development of kidney fibrosis, but its specific association with apoptosis or proliferation have yet to be determined. Objectives This study aims to determine the effects of unilateral ureteral obstruction (UUO) on proliferation, cellular senescence and apoptosis in kidney fibrosis. Methods A unilateral ureteral obstruction (UUO) procedure was performed to induce kidney fibrosis in 24 Swiss mice (3 months old, 30 g–40 g). Mice were sacrificed on day 3 (UUO3, n = 6), day 7 (UUO7, n = 6) and day 14 (UUO14, n = 6). Sham operation (SO) procedures were performed on the control group. The expression of Bcl-2, p16 and Bax mRNA was quantified with reverse transcription polymerase chain reaction (RT-PCR). Immunohistochemical (IHC) staining with anti-Bcl-2 and p53 antibodies was used to determine the localisation of proliferation and apoptosis. Data were analysed using one-way ANOVA followed by a post hoc least significant difference (LSD) test ( P < 0.05) Results RT-PCR analysis showed higher mRNA expression of Bcl-2, p16 and Bax in the UUO groups compared with SO group ( P < 0.05). Immunostaining showed that Bcl-2 and p53 expression in tubular epithelium in the UUO groups, except Bcl-2 expression was found in interstitial areas of UUO14 group. Conclusion Senescence in UUO might be associated with epithelial apoptosis and myofibroblast proliferation.

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“…In normal individuals, the number of nephrons is reduced with the age and fibroblast proliferates. Activated renal fibroblasts deposit excess extracellular matrix proteins, and kidney function declines [ 69 ]. This is the beginning of the deterioration of kidney structure and function that can lead to the final stages of CKD and even the need for renal replacement therapy such as dialysis or transplantation.…”

Section: Age Sex Pth Phosphate Fgf23 Klotho and Fibrosismentioning

confidence: 99%

Fibrosis in Chronic Kidney Disease: Pathogenesis and Consequences

Panizo

Martínez-Arias

Alonso-Montes

et al. 2021

IJMS

174

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Fibrosis is a process characterized by an excessive accumulation of the extracellular matrix as a response to different types of tissue injuries, which leads to organ dysfunction. The process can be initiated by multiple and different stimuli and pathogenic factors which trigger the cascade of reparation converging in molecular signals responsible of initiating and driving fibrosis. Though fibrosis can play a defensive role, in several circumstances at a certain stage, it can progressively become an uncontrolled irreversible and self-maintained process, named pathological fibrosis. Several systems, molecules and responses involved in the pathogenesis of the pathological fibrosis of chronic kidney disease (CKD) will be discussed in this review, putting special attention on inflammation, renin-angiotensin system (RAS), parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), Klotho, microRNAs (miRs), and the vitamin D hormonal system. All of them are key factors of the core and regulatory pathways which drive fibrosis, having a great negative kidney and cardiac impact in CKD.

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Aging, Cellular Senescence, and Kidney Fibrosis

Cited by 6 publications

References 106 publications

Development of a unilateral ureteral obstruction model in cynomolgus monkeys

Development of a unilateral ureteral obstruction model in cynomolgus monkeys

Upregulation of p16, Bax and Bcl-2 mRNAExpression Associated with Epithelial Apoptosis and Myofibroblast Proliferation in Kidney Fibrosis Model in Mice

Fibrosis in Chronic Kidney Disease: Pathogenesis and Consequences

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