scholarly journals Aristolochic Acid Induces Renal Fibrosis and Senescence in Mice

2021 ◽  
Vol 22 (22) ◽  
pp. 12432
Author(s):  
Shingo Urate ◽  
Hiromichi Wakui ◽  
Kengo Azushima ◽  
Takahiro Yamaji ◽  
Toru Suzuki ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Aristolochic Acid ◽  
Kidney Diseases ◽  
Functional Decline ◽  
Related Factors ◽  
Chronic Kidney Diseases ◽  
Age Related ◽  
Proximal Tubular ◽  
Renal Aging ◽  
Aging Kidney

The kidney is one of the most susceptible organs to age-related impairments. Generally, renal aging is accompanied by renal fibrosis, which is the final common pathway of chronic kidney diseases. Aristolochic acid (AA), a nephrotoxic agent, causes AA nephropathy (AAN), which is characterized by progressive renal fibrosis and functional decline. Although renal fibrosis is associated with renal aging, whether AA induces renal aging remains unclear. The aim of the present study is to investigate the potential use of AAN as a model of renal aging. Here, we examined senescence-related factors in AAN models by chronically administering AA to C57BL/6 mice. Compared with controls, the AA group demonstrated aging kidney phenotypes, such as renal atrophy, renal functional decline, and tubulointerstitial fibrosis. Additionally, AA promoted cellular senescence specifically in the kidneys, and increased renal p16 mRNA expression and senescence-associated β-galactosidase activity. Furthermore, AA-treated mice exhibited proximal tubular mitochondrial abnormalities, as well as reactive oxygen species accumulation. Klotho, an antiaging gene, was also significantly decreased in the kidneys of AA-treated mice. Collectively, the results of the present study indicate that AA alters senescence-related factors, and that renal fibrosis is closely related to renal aging.

scholarly journals Aristolochic Acid Nephropathy as a Potential Model of Renal Senescence

2021 ◽  
Author(s):  
Shingo Urate ◽  
Hiromichi Wakui ◽  
Kengo Azushima ◽  
Takahiro Yamaji ◽  
Toru Suzuki ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Potential Model ◽  
Aristolochic Acid ◽  
Functional Decline ◽  
Common Pathway ◽  
Aristolochic Acid Nephropathy ◽  
Proximal Tubular ◽  
Renal Aging ◽  
Renal Senescence ◽  
Aged Kidney

Abstract The kidney is among the organs most susceptible to age-associated impairments. Although there has recently been extensive research on renal aging, appropriate models remain limited. Generally, renal aging is strongly associated with renal fibrosis, which is the final common pathway of chronic kidney disease. Aristolochic acid (AA), a nephrotoxic agent, causes aristolochic acid nephropathy (AAN), characterized by progressive renal fibrosis and functional decline. Here, we examined the potential of AAN as a model of renal senescence by chronically administering AA to C57BL/6 mice. Compared with controls, the AA group presented aged kidney-like phenotypes such as renal atrophy, renal functional decline, and tubulointerstitial fibrosis. Additionally, AA promoted cellular senescence specifically in the kidney, concomitant with increase in renal p16 mRNA expression and senescence-associated β-galactosidase activity. Furthermore, AA-treated mice exhibited proximal tubular mitochondrial abnormalities, followed by accumulation of reactive oxygen species. Additionally, Klotho, an antiaging gene, was significantly decreased in the kidney of AA-treated mice. Collectively, the results of the present study indicate that AAN partially mimics the aged kidney and may serve as a useful mouse model for research on renal aging.

scholarly journals Role of tubular epithelial arginase-II in renal inflammaging

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ji Huang ◽  
Xiujie Liang ◽  
Diogo Ladeiras ◽  
Benoit Fellay ◽  
Xiu-Fen Ming ◽  
...  
Keyword(s):  
Aging Process ◽  
Kidney Diseases ◽  
Treatment And Prevention ◽  
Promising Therapeutic Target ◽  
Proximal Tubular ◽  
Arginase Ii ◽  
Renal Proximal Tubular ◽  
Renal Aging ◽  
Aging Kidney

AbstractThe aging kidney undergoes complex changes and is vulnerable to injury and development of chronic kidney disease (CKD) with preponderance affecting more women than men. Evidence has been presented that the type-II L-arginine:ureohydrolase, arginase-II (Arg-II) plays a role in the acceleration of aging. Arg-II is highly expressed in the kidney. However, the role of Arg-II in renal aging is not known. This study is to investigate whether Arg-II is involved in the kidney aging process dependently on sex. Arg-II level in the kidney of wild type (WT) mice is significantly elevated with aging, which is accompanied by an increase in expression of the inflammatory cytokines/chemokines, tissue macrophages, factors involved in fibrosis, and tubulointestitial fibrosis in both males and females. This renal aging phenotype is significantly suppressed in arg-II−/− mice, mainly in the females in which Arg-II level is higher than in the males. Importantly, numerous factors such as IL-1β, MCP1, VCAM-1, and TGFβ1 are mainly localized in the proximal tubular S3 segment cells expressing Arg-II in the aging kidney. In human proximal tubular cells (HK-2), TNF-α enhances adhesion molecule expression dependently on Arg-II upregulation. Overexpression of Arg-II in the cells enhances TGFβ1 levels which is prevented by mitochondrial ROS inhibition. In summary, our study reveals that renal proximal tubular Arg-II plays an important role in the kidney aging process in females. Arg-II could be a promising therapeutic target for the treatment and prevention of aging-associated kidney diseases.

scholarly journals Vascular and renal telomere shortening in mice exposed to chronic intermittent hypoxia

2021 ◽  
Author(s):  
Mohammad Badran ◽  
Bisher Abuyassin ◽  
Najib Ayas ◽  
Don D. Sin ◽  
Ismail Laher
Keyword(s):  
Obstructive Sleep Apnea ◽  
Chronic Condition ◽  
Intermittent Hypoxia ◽  
Kidney Diseases ◽  
Chronic Intermittent Hypoxia ◽  
Telomere Shortening ◽  
Chronic Kidney Diseases ◽  
Biomarkers Of Aging ◽  
Obstructive Sleep ◽  
Renal Aging

AbstractObstructive sleep apnea (OSA) is a chronic condition characterized by chronic intermittent hypoxia (IH) and is associated with cardiovascular (CVD) and chronic kidney diseases (CKD). There is increased biomarkers of aging, such as telomere shortening, in patients with OSA. We assessed telomere lengths in aortic and renal tissues from mice exposed to 8 weeks of IH using a PCR protocol, and demonstrate significant telomere shortening in both tissues. This data indicates that IH, a hallmark of OSA, can accelerate vascular and renal aging that may contribute to OSA-induced CVD and CKD

scholarly journals Mesenchymal stem cells ameliorate renal fibrosis by galectin-3/Akt/GSK3β/Snail signaling pathway in adenine-induced nephropathy rat

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Huajun Tang ◽  
Peiyue Zhang ◽  
Lianlin Zeng ◽  
Yu Zhao ◽  
Libo Xie ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Renal Fibrosis ◽  
Lentiviral Vector ◽  
Kidney Diseases ◽  
Collagen Type I ◽  
Type I ◽  
Chronic Kidney Diseases ◽  
Galectin 3 ◽  
Tgf Β1 ◽  
Sirius Red

Abstract Background Tubulointerstitial fibrosis (TIF) is one of the main pathological features of various progressive renal damages and chronic kidney diseases. Mesenchymal stromal cells (MSCs) have been verified with significant improvement in the therapy of fibrosis diseases, but the mechanism is still unclear. We attempted to explore the new mechanism and therapeutic target of MSCs against renal fibrosis based on renal proteomics. Methods TIF model was induced by adenine gavage. Bone marrow-derived MSCs was injected by tail vein after modeling. Renal function and fibrosis related parameters were assessed by Masson, Sirius red, immunohistochemistry, and western blot. Renal proteomics was analyzed using iTRAQ-based mass spectrometry. Further possible mechanism was explored by transfected galectin-3 gene for knockdown (Gal-3 KD) and overexpression (Gal-3 OE) in HK-2 cells with lentiviral vector. Results MSCs treatment clearly decreased the expression of α-SMA, collagen type I, II, III, TGF-β1, Kim-1, p-Smad2/3, IL-6, IL-1β, and TNFα compared with model rats, while p38 MAPK increased. Proteomics showed that only 40 proteins exhibited significant differences (30 upregulated, 10 downregulated) compared MSCs group with the model group. Galectin-3 was downregulated significantly in renal tissues and TGF-β1-induced rat tubular epithelial cells and interstitial fibroblasts, consistent with the iTRAQ results. Gal-3 KD notably inhibited the expression of p-Akt, p-GSK3β and snail in TGF-β1-induced HK-2 cells fibrosis. On the contrary, Gal-3 OE obviously increased the expression of p-Akt, p-GSK3β and snail. Conclusion The mechanism of MSCs anti-renal fibrosis was probably mediated by galectin-3/Akt/GSK3β/Snail signaling pathway. Galectin-3 may be a valuable target for treating renal fibrosis.

scholarly journals Extracellular Matrix in Kidney Fibrosis: More Than Just a Scaffold

2019 ◽  
Vol 67 (9) ◽  
pp. 643-661 ◽  
Author(s):  
Roman David Bülow ◽  
Peter Boor
Keyword(s):  
Extracellular Matrix ◽  
Renal Fibrosis ◽  
Kidney Diseases ◽  
Dynamic Structure ◽  
Renal Diseases ◽  
Chronic Kidney Diseases ◽  
Kidney Fibrosis ◽  
Non Invasive ◽  
Ecm Proteins ◽  
Diagnostic Approaches

Kidney fibrosis is the common histological end-point of progressive, chronic kidney diseases (CKDs) regardless of the underlying etiology. The hallmark of renal fibrosis, similar to all other organs, is pathological deposition of extracellular matrix (ECM). Renal ECM is a complex network of collagens, elastin, and several glycoproteins and proteoglycans forming basal membranes and interstitial space. Several ECM functions beyond providing a scaffold and organ stability are being increasingly recognized, for example, in inflammation. ECM composition is determined by the function of each of the histological compartments of the kidney, that is, glomeruli, tubulo-interstitium, and vessels. Renal ECM is a dynamic structure undergoing remodeling, particularly during fibrosis. From a clinical perspective, ECM proteins are directly involved in several rare renal diseases and indirectly in CKD progression during renal fibrosis. ECM proteins could serve as specific non-invasive biomarkers of fibrosis and scaffolds in regenerative medicine. The gold standard and currently only specific means to measure renal fibrosis is renal biopsy, but new diagnostic approaches are appearing. Here, we discuss the localization, function, and remodeling of major renal ECM components in healthy and diseased, fibrotic kidneys and the potential use of ECM in diagnostics of renal fibrosis and in tissue engineering.

scholarly journals Janus-Faced: Molecular Mechanisms and Versatile Nature of Renal Fibrosis

Kidney360 ◽  
2020 ◽  
Vol 1 (7) ◽  
pp. 697-704
Author(s):  
Hiroyuki Arai ◽  
Motoko Yanagita
Keyword(s):  
Renal Fibrosis ◽  
Molecular Mechanisms ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Lymphoid Tissues ◽  
Functional Heterogeneity ◽  
Current Perspective ◽  
Proximal Tubular ◽  
Kidney Disease Progression ◽  
Injury And Repair

Renal fibrosis is a major hallmark of CKD, regardless of the underlying etiology. In fibrosis development and progression, myofibroblasts play a pivotal role, producing extracellular matrix and interacting with various resident cells in the kidney. Over the past decade, the origin of myofibroblasts has been thoroughly investigated. Emerging evidence suggests that renal myofibroblasts originate from several cellular sources, including resident fibroblasts, pericytes, and bone marrow–derived cells. The contribution of resident fibroblasts is most crucial, and currently available data strongly suggest the importance of functional heterogeneity and plasticity of fibroblasts in kidney disease progression. Resident fibroblasts acquire distinct phenotypes based on their local microenvironment and exert multifactorial functions. For example, age-dependent alterations of renal fibroblasts make a significant contribution to the formation of tertiary lymphoid tissues, which promote local inflammation after injury in the aged kidney. In conjunction with fibrosis development, dysfunction of resident fibroblasts provokes unique pathologic conditions including renal anemia and peritubular capillary loss, both of which are major complications of CKD. Although renal fibrosis is considered detrimental in general, recent studies suggest it has beneficial roles, such as maintaining functional crosstalk with injured proximal tubular cells and supporting their regeneration. These findings provide novel insight into the mechanisms of renal fibrosis, which could be regarded as an adaptive process of kidney injury and repair. Precise understanding of the functional heterogeneity of resident fibroblasts and myofibroblasts has the potential to facilitate the development of novel therapeutics against kidney diseases. In this review, we describe the current perspective on the origin of myofibroblasts and fibroblast heterogeneity, with special emphasis on the dual aspects of renal fibrosis, both beneficial and detrimental, in CKD progression.

scholarly journals Urinary C-type natriuretic peptide excretion: a potential novel biomarker for renal fibrosis during aging

2011 ◽  
Vol 301 (5) ◽  
pp. F943-F952 ◽  
Author(s):  
S. Jeson Sangaralingham ◽  
Denise M. Heublein ◽  
Joseph P. Grande ◽  
Alessandro Cataliotti ◽  
Andrew D. Rule ◽  
...  
Keyword(s):  
Natriuretic Peptide ◽  
Renal Fibrosis ◽  
Structural Changes ◽  
Microscopic Analysis ◽  
The Elderly ◽  
Electron Microscopic ◽  
Functional Changes ◽  
Age Related ◽  
Increased Risk ◽  
Renal Aging

Renal aging is characterized by structural changes in the kidney including fibrosis, which contributes to the increased risk of kidney and cardiac failure in the elderly. Studies involving healthy kidney donors demonstrated subclinical age-related nephropathy on renal biopsy that was not detected by standard diagnostic tests. Thus there is a high-priority need for novel noninvasive biomarkers to detect the presence of preclinical age-associated renal structural and functional changes. C-type natriuretic peptide (CNP) possesses renoprotective properties and is present in the kidney; however, its modulation during aging remains undefined. We assessed circulating and urinary CNP in a Fischer rat model of experimental aging and also determined renal structural and functional adaptations to the aging process. Histological and electron microscopic analysis demonstrated significant renal fibrosis, glomerular basement membrane thickening, and mesangial matrix expansion with aging. While plasma CNP levels progressively declined with aging, urinary CNP excretion increased, along with the ratio of urinary to plasma CNP, which preceded significant elevations in proteinuria and blood pressure. Also, CNP immunoreactivity was increased in the distal and proximal tubules in both the aging rat and aging human kidneys. Our findings provide evidence that urinary CNP and its ratio to plasma CNP may represent a novel biomarker for early age-mediated renal structural alterations, particularly fibrosis. Thus urinary CNP could potentially aid in identifying subjects with preclinical structural changes before the onset of symptoms and disease, allowing for the initiation of strategies designed to prevent the progression of chronic kidney disease particularly in the aging population.

scholarly journals Effects of HIF-1α on renal fibrosis in cisplatin-induced chronic kidney disease

2021 ◽  
Author(s):  
Hao Zhao ◽  
Yu Liu ◽  
Yachun Han ◽  
Na Jiang ◽  
Chenrui Li ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Kidney Diseases ◽  
Gene Knockout ◽  
Notch 1 ◽  
Primary Mouse ◽  
Proximal Tubular ◽  
In Cis

Cisplatin (Cis) can cause chronic kidney disease (CKD) and promote renal fibrosis, but the underlying mechanism is not fully understood. Hypoxia inducible factor-1α (HIF-1α) can promote renal fibrosis in some kidney diseases, but its role in Cis-induced CKD is still unknown. Notch-1 is a recognized molecule that promotes renal fibrosis under pathological circumstances, and evidence shows that HIF-1α and Notch-1 are closely related to each other. In the present study, mice with HIF-1α gene knockout in proximal tubular cells (PTCs) (PT-HIF-1α-KO) were generated and treated with Cis to induce CKD. A human proximal tubular cell line (HK-2) and primary mouse PTCs were used for in vitro studies. The results showed that HIF-1α was increased in the kidneys of Cis-treated wild-type mice, accompanied by elevated Notch-1, Notch-1 intracellular domain (N1ICD), Hes-1 and renal fibrosis. However, these alterations were partially reversed in PT-HIF-1α-KO mice. Similar results were observed in HK-2 cells and primary mouse PTCs. In addition, treating the cells with Cis induced a marked interaction of HIF-1α and N1ICD. Further inhibiting Notch-1 significantly reduced cellular fibrogenesis but did not affect HIF-1α expression. The data suggested that HIF-1α could promote renal fibrosis in Cis-induced CKD by activating Notch-1 both transcriptionally and posttranscriptionally and that HIF-1α may serve as a potential therapeutic target for Cis-induced CKD.

scholarly journals Autophagy in Chronic Kidney Diseases

Cells ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 61 ◽  
Author(s):  
Tien-An Lin ◽  
Victor Chien-Chia Wu ◽  
Chao-Yung Wang
Keyword(s):  
Kidney Diseases ◽  
Kidney Injury ◽  
Current Evidence ◽  
Polycystic Kidney ◽  
Recycling Process ◽  
Chronic Kidney Diseases ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Cellular Regeneration ◽  
Molecular Aspects

Autophagy is a cellular recycling process involving self-degradation and reconstruction of damaged organelles and proteins. Current evidence suggests that autophagy is critical in kidney physiology and homeostasis. In clinical studies, autophagy activations and inhibitions are linked to acute kidney injuries, chronic kidney diseases, diabetic nephropathies, and polycystic kidney diseases. Oxidative stress, inflammation, and mitochondrial dysfunction, which are implicated as important mechanisms underlying many kidney diseases, modulate the autophagy activation and inhibition and lead to cellular recycling dysfunction. Abnormal autophagy function can induce loss of podocytes, damage proximal tubular cells, and glomerulosclerosis. After acute kidney injuries, activated autophagy protects tubular cells from apoptosis and enhances cellular regeneration. Patients with chronic kidney diseases have impaired autophagy that cannot be reversed by hemodialysis. Multiple nephrotoxic medications also alter the autophagy signaling, by which the mechanistic insights of the drugs are revealed, thus providing the unique opportunity to manage the nephrotoxicity of these drugs. In this review, we summarize the current concepts of autophagy and its molecular aspects in different kidney cells pathophysiology. We also discuss the current evidence of autophagy in acute kidney injury, chronic kidney disease, toxic effects of drugs, and aging kidneys. In addition, we examine therapeutic possibilities targeting the autophagy system in kidney diseases.

scholarly journals Elastin imaging enables noninvasive staging and treatment monitoring of kidney fibrosis

2019 ◽  
Vol 11 (486) ◽  
pp. eaat4865 ◽  
Author(s):  
Qinxue Sun ◽  
Maike Baues ◽  
Barbara M. Klinkhammer ◽  
Josef Ehling ◽  
Sonja Djudjaj ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Matrix Protein ◽  
Kidney Diseases ◽  
Therapeutic Interventions ◽  
Extracellular Matrix Protein ◽  
Imaging Method ◽  
Chronic Kidney Diseases ◽  
Kidney Fibrosis ◽  
Common Endpoint ◽  
Routine Assessment

Fibrosis is the common endpoint and currently the best predictor of progression of chronic kidney diseases (CKDs). Despite several drawbacks, biopsies remain the only available means to specifically assess the extent of renal fibrosis. Here, we show that molecular imaging of the extracellular matrix protein elastin allows for noninvasive staging and longitudinal monitoring of renal fibrosis. Elastin was hardly expressed in healthy mouse, rat, and human kidneys, whereas it was highly up-regulated in cortical, medullar, and perivascular regions in progressive CKD. Compared to a clinically relevant control contrast agent, the elastin-specific magnetic resonance imaging agent ESMA specifically detected elastin expression in multiple mouse models of renal fibrosis and also in fibrotic human kidneys. Elastin imaging allowed for repetitive and reproducible assessment of renal fibrosis, and it enabled longitudinal monitoring of therapeutic interventions, accurately capturing anti-fibrotic therapy effects. Last, in a model of reversible renal injury, elastin imaging detected ensuing fibrosis not identifiable via routine assessment of kidney function. Elastin imaging thus has the potential to become a noninvasive, specific imaging method to assess renal fibrosis.

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