Apoptosis, Fibrosis and Senescence

Portilla, Didier

doi:10.1159/000363717

Cited by 32 publications

(21 citation statements)

References 15 publications

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“…Senescent cells are prominent in PT and TAL in the cortex, and weakly in DT and CD in the outer medulla in the kidney of WT mice. This pattern is consistent with the fact that these kidney segments are the most susceptible to kidney insults (Portilla, 2014;Kefaloyianni et al, 2016;Kramann et al, 2017) and putative sites of EMT (Liu, 2004;Portilla, 2014;Gewin, 2018). Therefore, senescence in kidney tubules may be one of the mediator of cellular injury and plasticity of kidney epithelial cells after exposure to kidney insults (Kang and Johnson, 2003;Basile, 2007;Meran and Steadman, 2011;Humphreys, 2018).…”

Section: High Pi and Low Klotho Are Associated With High Senescence Isupporting

confidence: 84%

High Phosphate Induces and Klotho Attenuates Kidney Epithelial Senescence and Fibrosis

et al. 2020

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Cellular senescence is an irreversible cell growth arrest and is associated with aging and age-related diseases. High plasma phosphate (Pi) and deficiency of Klotho contribute to aging and kidney fibrosis, a pathological feature in the aging kidney and chronic kidney disease. This study examined the interactive role of Pi and Klotho in kidney senescence and fibrosis. Homozygous Klotho hypomorphic mice had high plasma Pi, undetectable Klotho in plasma and kidney, high senescence with massive collagen accumulation in kidney tubules, and fibrin deposits in peritubular capillaries. To examine the Pi effect on kidney senescence, a high (2%) Pi diet was given to wild-type mice. One week of high dietary Pi mildly increased plasma Pi, and upregulated kidney p16/p21 expression, but did not significantly decrease Klotho. Two weeks of high Pi intake led to increase in plasminogen activator inhibitor (PAI)-1, and decrease in kidney Klotho, but still without detectable increase in kidney fibrosis. More prolonged dietary Pi for 12 weeks exacerbated kidney senescence and fibrosis; more so in heterozygous Klotho hypomorphic mice compared to wild-type mice, and in mice with chronic kidney disease (CKD) on high Pi diet compared to CKD mice fed a normal Pi diet. In cultured kidney tubular cells, high Pi directly induced cellular senescence, injury and epithelialmesenchymal transition, and enhanced H 2 O 2-induced cellular senescence and injury, which were abrogated by Klotho. Fucoidan, a bioactive molecule with multiple biologic functions including senescence inhibition, blunted Pi-induced cellular senescence, oxidation, injury, epithelial-mesenchymal transition, and senescence-associated secretary phenotype. In conclusion, high Pi activates senescence through distinct but interconnected mechanisms: upregulating p16/p21 (early), and elevating plasminogen activator inhibitor-1 and downregulating Klotho (late). Klotho may be a promising agent to attenuate senescence and ameliorate age-associated, and Pi-induced kidney degeneration such as kidney fibrosis.

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Section: High Pi and Low Klotho Are Associated With High Senescence Isupporting

confidence: 84%

High Phosphate Induces and Klotho Attenuates Kidney Epithelial Senescence and Fibrosis

et al. 2020

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“…There was a linear relationship between aging and a decline in renal function. The expression of collagen IV was showed age-related increases in 24 and 30-month-old rats 5 . It is well known that ECM accumulation is the ultimately pathway to cause renal fibrosis with aging 3 , 19 .…”

Section: Discussionmentioning

confidence: 90%

“…Renal fibrosis was a major damage of age-related progressive kidney disease 3 , 4 . The cellular mechanisms that lead to age-related renal fibrosis were complex including inflammation, oxidative stress, apoptosis and senescence 5 . Therefore, the efficient therapeutic strategies were great significance in the control of age-related renal fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Amelioratory Effects of Testosterone Propionate on Age-related Renal Fibrosis via Suppression of TGF-β1/Smad Signaling and Activation of Nrf2-ARE Signaling

Zhang

Kang

Zhou

et al. 2018

Sci Rep

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Androgen plays a pivotal role in the progression of renal fibrosis. However, whether exogenous androgen treatment to aged male rats can improve the age-related renal fibrosis was not explored. In our study, the changes of morphological structure, renal fibrosis, ultrastructure and renal function, the expressions of extracellular matrix (ECM), matrix metalloproteinases (MMPs) and its tissue inhibitors of metalloproteinases (TIMPs), the expressions of tumor growth factor β1 (TGF-β1)/Smad signaling and oxidative stress parameters as well as nuclear factor erythroid 2-related factor 2-antioxidant response element (Nrf2-ARE) signaling were tested in kidney of aged male Wistar rats after subcutaneous testosterone propionate (TP, 2 mg/kg/d, 84-day) injection. Aged rats showed significantly renal histopathological changes, increased renal fibrosis, increased thickening of the glomerular basement membrane and the Bowman’s capsule basement membrane, declined renal functional, increased ECM, lower expressions of MMP-2 and MMP-9 and higher expressions of TIMP-1 and TIMP-2 in renal tissues and higher expressions of TGF-β1/Smad signaling, as well as lower expressions of Nrf2-ARE signaling compared to young rats. TP treatment significantly improved age-related above indexes. These results suggested that TP supplement may alleviate age-related renal fibrosis via suppression of TGF-β1/Smad signaling and activation of Nrf2-ARE signaling in aged rats.

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“…Chronic kidney disease (CKD), particularly in advanced stages, is considered one of the most serious public health problems worldwide [1,2].For a long time, efforts have been made understand the risk factors associated to the development of kidney fibrosis, since it is considered one of the most potent risk factors for CKD progression, independent from the CKD etiology, as it represents a final common pathway from injury [3].The tubules and interstitial compartment together constitute approximately 80% of the renal mass and is, therefore, more than a complex support system structures [4][5][6].There are three main recognized histological structures that can be assessed for fibrosis: glomerulosclerosis, vascular sclerosis andtubular atrophy/tubulointerstitial fibrosis (IFTA) [7,8].IFTA is the final result of an anatomic and functional imbalance where the kidney insults exceed the known compensatory mechanisms of repair where different mediators generate the transition from the normal tubular structure to myofibroblasts and elements of the extracellular matrix [9,10]. At this point changes are irreversible and therefore strongly associated to kidney disease progression [11].Trials performed in patients undergoing kidney transplantation suggest that IFTA is strongly implicated with graft failure, progression, and increased mortality [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Furosemide stress test and interstitial fibrosis in kidney biopsies in chronic kidney disease

et al. 2020

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Background: Interstitial fibrosis (IF) on kidney biopsy is one of the most potent risk factors for kidney disease progression. The furosemide stress test (FST) is a validated tool that predicts the severity of acute kidney injury (especially at 2 h) in critically ill patients. Since furosemide is secreted through the kidney tubules, the response to FST represents the tubular secretory capacity. To our knowledge there is no data on the correlation between functional tubular capacity assessed by the FST with IF on kidney biopsies from patients with chronic kidney disease (CKD). The aim of this study was to determine the association between urine output (UO), Furosemide Excreted Mass (FEM) and IF on kidney biopsies after a FST. Methods: This study included 84 patients who underwent kidney biopsy for clinical indications and a FST. The percentage of fibrosis was determined by morphometry technique and reviewed by a nephropathologist. All patients underwent a FST prior to the biopsy. Urine volume and urinary sodium were measured in addition to urine concentrations of furosemide at different times (2, 4 and 6 h). We used an established equation to determine the FEM. Values were expressed as mean, standard deviation or percentage and Pearson Correlation. Results: The mean age of the participants was 38 years and 44% were male. The prevalence of diabetes mellitus, hypertension and diuretic use was significantly higher with more advanced degree of fibrosis. Nephrotic syndrome and acute kidney graft dysfunction were the most frequent indications for biopsy. eGFR was inversely related to the degree of fibrosis. Subjects with the highest degree of fibrosis (grade 3) showed a significant lower UO at first hour of the FST when compared to lower degrees of fibrosis (p = 0.015). Likewise, the total UO and the FEM was progressively lower with higher degrees of fibrosis. An inversely linear correlation between FEM and the degree of fibrosis (r = − 0.245, p = 0.02) was observed. Conclusions: Our findings indicate that interstitial fibrosis correlates with total urine output and FEM. Further studies are needed to determine if UO and FST could be a non-invasive tool to evaluate interstitial fibrosis. Trial registration: ClinicalTrials.gov NCT02417883.

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Apoptosis, Fibrosis and Senescence

Cited by 32 publications

References 15 publications

High Phosphate Induces and Klotho Attenuates Kidney Epithelial Senescence and Fibrosis

High Phosphate Induces and Klotho Attenuates Kidney Epithelial Senescence and Fibrosis

Amelioratory Effects of Testosterone Propionate on Age-related Renal Fibrosis via Suppression of TGF-β1/Smad Signaling and Activation of Nrf2-ARE Signaling

Furosemide stress test and interstitial fibrosis in kidney biopsies in chronic kidney disease

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