scholarly journals Cordyceps cicadae Prevents Renal Tubular Epithelial Cell Apoptosis by Regulating the SIRT1/p53 Pathway in Hypertensive Renal Injury

2020 ◽  
Vol 2020 ◽  
pp. 1-13 ◽  
Author(s):  
Yi Shan Huang ◽  
Xu Wang ◽  
Zhendong Feng ◽  
Hailan Cui ◽  
Zebing Zhu ◽  
...  
Keyword(s):  
Renal Injury ◽  
Spontaneously Hypertensive Rat ◽  
Interstitial Fibrosis ◽  
Kidney Diseases ◽  
Smooth Muscle Actin ◽  
Chinese Herb ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
P53 Pathway ◽  
Cordyceps Cicadae

Hypertensive renal injury is a primary etiology of end-stage renal disease, and satisfactory therapeutic strategies are urgently required. Cordyceps cicadae, a traditional Chinese herb, has potential renoprotective benefits and is widely used in the treatment of many kidney diseases. To investigate the mechanisms underlying the renoprotective effect of C. cicadae on hypertensive renal injury, we studied the effect of C. cicadae on tubular epithelial cells (TECs) in a spontaneously hypertensive rat (SHR) model and angiotensin II- (AngII-) cultured primary TECs. Our study showed that C. cicadae treatment could decrease 24-hour urine albumin, albumin-to-creatinine ratio (ACR), β2-MG level, and kidney injury molecule-1 (kim-1) level in SHR urine, alleviate interstitial fibrosis, and reduce α-smooth muscle actin (α-SMA) expression in SHR kidney. In primary TECs, medicated serum containing C. cicadae (CSM) might significantly reduce the AngII-induced production of kim-1 and neutrophil gelatinase-associated lipocalin (NGAL). Furthermore, C. cicadae treatment could decrease TEC apoptosis in SHRs as assessed by the terminal transferase-mediated biotin dUTP nick-end labeling (TUNEL) assay. CSM could inhibit caspase-3 activity and enhance cellular viability as measured by methyl thiazolyl tetrazolium in AngII-cultured TECs, suggesting that CSM might reduce the apoptosis level in TECs induced by AngII. We found that the SIRT1 expression level was markedly lowered, while the protein level of acetylated-p53 was elevated in the TECs of patients with hypertensive renal injury and SHRs. C. cicadae presented the effect of regulating the SIRT1/p53 pathway. Further SIRT1 inhibition with EX527 reversed the effect of C. cicadae on AngII-induced apoptosis. Taken together, our results indicate that C. cicadae offers a protective effect on TECs under hypertensive conditions, which may be related to its antiapoptotic effect through regulation of the SIRT1/p53 pathway.

scholarly journals Targeting Ferroptosis Attenuates Interstitial Inflammation and Kidney Fibrosis

2021 ◽  
pp. 1-15
Author(s):  
Lu Zhou ◽  
Xian Xue ◽  
Qing Hou ◽  
Chunsun Dai
Keyword(s):  
Mouse Models ◽  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
Kidney Fibrosis ◽  
Ureter Obstruction ◽  
Regulated Necrosis ◽  
Dependent Form

<b><i>Background:</i></b> Ferroptosis, an iron-dependent form of regulated necrosis mediated by lipid peroxidation, predominantly polyunsaturated fatty acids, is involved in postischemic and toxic kidney injury. However, the role and mechanisms for tubular epithelial cell (TEC) ferroptosis in kidney fibrosis remain largely unknown. <b><i>Objectives:</i></b> The aim of the study was to decipher the role and mechanisms for TEC ferroptosis in kidney fibrosis. <b><i>Methods:</i></b> Mouse models with unilateral ureter obstruction (UUO) or ischemia/reperfusion injury (IRI) were generated. <b><i>Results:</i></b> We found that TEC ferroptosis exhibited as reduced glutathione peroxidase 4 (GPX4) expression and increased 4-hydroxynonenal abundance was appeared in kidneys from chronic kidney disease (CKD) patients and mouse models with UUO or IRI. Inhibition of ferroptosis could largely mitigate kidney injury, interstitial fibrosis, and inflammatory cell accumulation in mice after UUO or IRI. Additionally, treatment of TECs with (1S,3R)-RSL-3, an inhibitor of GPX4, could enhance cell ferroptosis and recruit macrophages. Furthermore, inhibiting TEC ferroptosis reduced monocyte chemotactic protein 1 (MCP-1) secretion and macrophage chemotaxis. <b><i>Conclusions:</i></b> This study uncovers that TEC ferroptosis may promote interstitial fibrosis and inflammation, and targeting ferroptosis may shine a light on protecting against kidney fibrosis in patients with CKDs.

scholarly journals Inhibition of histone deacetylase activity attenuates renal fibroblast activation and interstitial fibrosis in obstructive nephropathy

2009 ◽  
Vol 297 (4) ◽  
pp. F996-F1005 ◽  
Author(s):  
Maoyin Pang ◽  
Jagan Kothapally ◽  
Haiping Mao ◽  
Evelyn Tolbert ◽  
Murugavel Ponnusamy ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Interstitial Fibrosis ◽  
Kidney Diseases ◽  
Trichostatin A ◽  
Smooth Muscle Actin ◽  
Tubular Cell ◽  
Obstructive Nephropathy ◽  
Renal Tubular Cell ◽  
Fibroblast Activation ◽  
Renal Tubular

Activation of renal interstitial fibroblasts is critically involved in the development of tubulointerstitial fibrosis in chronic kidney diseases. In this study, we investigated the effect of trichostatin A (TSA), a specific histone deacetylase (HDAC) inhibitor, on the activation of renal interstitial fibroblasts in a rat renal interstitial fibroblast line (NRK-49F) and the development of renal fibrosis in a murine model of unilateral ureteral obstruction (UUO) . α-Smooth muscle actin (α-SMA) and fibronectin, two hallmarks of fibroblast activation, were highly expressed in cultured NRK-49F cells, and their expression was inhibited in the presence of TSA. Similarly, administration of TSA suppressed the expression of α-SMA and fibronectin and attenuated the accumulation of renal interstitial fibroblasts in the kidney after the obstructive injury. Activation of renal interstitial fibroblasts was accompanied by phosphorylation of signal transducer and activator of transcription 3 (STAT3), and TSA treatment also abolished these responses. Furthermore, inhibition of the STAT3 pathway with AG490 inhibited expression of α-SMA and fibronectin in NRK-49F cells. Finally, TSA treatment inhibited tubular cell apoptosis and caspase-3 activation in the obstructive kidney. Collectively, we suggest that pharmacological HDAC inhibition may induce antifibrotic activity by inactivation of renal interstitial fibroblasts and inhibition of renal tubular cell death. STAT3 may mediate those actions of HDACs.

Ovariectomy is protective against renal injury in the high-salt-fed older mRen2.Lewis rat

2007 ◽  
Vol 293 (4) ◽  
pp. H2064-H2071 ◽  
Author(s):  
Liliya M. Yamaleyeva ◽  
Karl D. Pendergrass ◽  
Nancy T. Pirro ◽  
Patricia E. Gallagher ◽  
Leanne Groban ◽  
...  
Keyword(s):  
Renal Injury ◽  
Interstitial Fibrosis ◽  
Kidney Injury ◽  
High Salt ◽  
Glomerular Sclerosis ◽  
Tubular Damage ◽  
Lewis Rat ◽  
Lewis Rats ◽  
Ovx Rats ◽  
Igf I

Studies in experimental animals and younger women suggest a protective role for estrogen; however, clinical trials may not substantiate this effect in older females. Therefore, the present study assessed the outcome of ovariectomy in older mRen2.Lewis rats subjected to a high-salt diet for 4 wk. Intact or ovariectomized (OVX, 15 wk of age) mRen2.Lewis rats were aged to 60 wk and then placed on a high-salt (HS, 8% sodium chloride) diet for 4 wk. Systolic blood pressures were similar between groups [OVX 169 ± 6 vs. Intact 182 ± 7 mmHg; P = 0.22] after the 4-wk diet; however, proteinuria [OVX 0.8 ± 0.2 vs. Intact 11.5 ± 2.6 mg/mg creatinine; P < 0.002, n = 6], renal interstitial fibrosis, glomerular sclerosis, and tubular casts were lower in OVX vs. Intact rats. Kidney injury molecule-1 mRNA, a marker of tubular damage, was 53% lower in the OVX HS group. Independent from blood pressure, OVX HS rats exhibited significantly lower cardiac (24%) and renal (32%) hypertrophy as well as lower C-reactive protein (28%). Circulating insulin-like growth factor-I (IGF-I) levels were not different between the Intact and OVX groups; however, renal cortical IGF-I mRNA and protein were attenuated in OVX rats [ P < 0.05, n = 6]. We conclude that ovariectomy in the older female mRen2.Lewis rat conveys protection against salt-dependent increase in renal injury.

scholarly journals Targeting the RNA-Binding Protein QKI in Myeloid Cells Ameliorates Macrophage-Induced Renal Interstitial Fibrosis

Epigenomes ◽  
2020 ◽  
Vol 4 (1) ◽  
pp. 2
Author(s):  
Ruben G. de Bruin ◽  
Gillian Vogel ◽  
Jurrien Prins ◽  
Jacques M. J. G. Duijs ◽  
Roel Bijkerk ◽  
...  
Keyword(s):  
Rna Binding ◽  
Interstitial Fibrosis ◽  
Kidney Diseases ◽  
Cell Lineage ◽  
Kidney Injury ◽  
Myeloid Cell ◽  
Mrna Splicing ◽  
Transcriptional Level ◽  
Renal Interstitial Fibrosis ◽  
Splice Regulator

In the pathophysiologic setting of acute and chronic kidney injury, the excessive activation and recruitment of blood-borne monocytes prompts their differentiation into inflammatory macrophages, a process that leads to progressive glomerulosclerosis and interstitial fibrosis. Importantly, this differentiation of monocytes into macrophages requires the meticulous coordination of gene expression at both the transcriptional and post-transcriptional level. The transcriptomes of these cells are ultimately determined by RNA-binding proteins such as QUAKING (QKI), that define their pre-mRNA splicing and mRNA transcript patterns. Using two mouse models, namely (1) quaking viable mice (qkv) and (2) the conditional deletion in the myeloid cell lineage using the lysozyme 2-Cre (QKIFL/FL;LysM-Cre mice), we demonstrate that the abrogation of QKI expression in the myeloid cell lineage reduces macrophage infiltration following kidney injury induced by unilateral urethral obstruction (UUO). The qkv and QKIFL/FL;LysM-Cre mice both showed significant diminished interstitial collagen deposition and fibrosis in the UUO-damaged kidney, as compared to wild-type littermates. We show that macrophages isolated from QKIFL/FL;LysM-Cre mice are associated with defects in pre-mRNA splicing. Our findings demonstrate that reduced expression of the alternative splice regulator QKI in the cells of myeloid lineage attenuates renal interstitial fibrosis, suggesting that inhibition of this splice regulator may be of therapeutic value for certain kidney diseases.

Diabetic nephropathy – is this an immune disorder?

2017 ◽  
Vol 131 (16) ◽  
pp. 2183-2199 ◽  
Author(s):  
Greg H. Tesch
Keyword(s):  
Immune Response ◽  
Diabetic Nephropathy ◽  
Immune System ◽  
Renal Injury ◽  
Kidney Diseases ◽  
Critical Role ◽  
Kidney Injury ◽  
Immune Disorder ◽  
Patients With Diabetes ◽  
Stage Renal Disease

Chronic diabetes is associated with metabolic and haemodynamic stresses which can facilitate modifications to DNA, proteins and lipids, induce cellular dysfunction and damage, and stimulate inflammatory and fibrotic responses which lead to various types of renal injury. Approximately 30–40% of patients with diabetes develop nephropathy and this renal injury normally progresses in about a third of patients. Due to the growing incidence of diabetes, diabetic nephropathy is now the main cause of end-stage renal disease (ESRD) worldwide. Accumulating evidence from experimental and clinical studies has demonstrated that renal inflammation plays a critical role in determining whether renal injury progresses during diabetes. However, the immune response associated with diabetic nephropathy is considerably different to that seen in autoimmune kidney diseases or in acute kidney injury arising from episodes of ischaemia or infection. This review evaluates the role of the immune system in the development of diabetic nephropathy, including the specific contributions of leucocyte subsets (macrophages, neutrophils, mast cells, T and B lymphocytes), danger-associated molecular patterns (DAMPs), inflammasomes, immunoglobulin and complement. It also examines factors which may influence the development of the immune response, including genetic factors and exposure to other kidney insults. In addition, this review discusses therapies which are currently under development for targeting the immune system in diabetic nephropathy and indicates those which have proceeded into clinical trials.

scholarly journals Silencing of hypoxia-inducible factor-1α gene attenuates chronic ischemic renal injury in two-kidney, one-clip rats

2014 ◽  
Vol 306 (10) ◽  
pp. F1236-F1242 ◽  
Author(s):  
Zhengchao Wang ◽  
Qing Zhu ◽  
Pin-Lan Li ◽  
Romesh Dhaduk ◽  
Fan Zhang ◽  
...  
Keyword(s):  
Renal Artery ◽  
Renal Injury ◽  
Protective Factor ◽  
Kidney Diseases ◽  
Smooth Muscle Actin ◽  
Hypoxia Inducible Factor ◽  
Left Renal Artery ◽  
Pathogenic Factor ◽  
Control Vector ◽  
Protein Levels

Overactivation of hypoxia-inducible factor (HIF)-1α is implicated as a pathogenic factor in chronic kidney diseases (CKD). However, controversy exists regarding the roles of HIF-1α in CKD. Additionally, although hypoxia and HIF-1α activation are observed in various CKD and HIF-1α has been shown to stimulate fibrogenic factors, there is no direct evidence whether HIF-1α is an injurious or protective factor in chronic renal hypoxic injury. The present study determined whether knocking down the HIF-1α gene can attenuate or exaggerate kidney damage using a chronic renal ischemic model. Chronic renal ischemia was induced by unilaterally clamping the left renal artery for 3 wk in Sprague-Dawley rats. HIF-1α short hairpin (sh) RNA or control vectors were transfected into the left kidneys. Experimental groups were sham+control vector, clip+control vector, and clip+HIF-1α shRNA. Enalapril was used to normalize blood pressure 1 wk after clamping the renal artery. HIF-1α protein levels were remarkably increased in clipped kidneys, and this increase was blocked by shRNA. Morphological examination showed that HIF-1α shRNA significantly attenuated injury in clipped kidneys: glomerular injury indices were 0.71 ± 0.04, 2.50 ± 0.12, and 1.34 ± 0.11, and the percentage of globally damaged glomeruli was 0.02, 34.3 ± 5.0, and 6.3 ± 1.6 in sham, clip, and clip+shRNA groups, respectively. The protein levels of collagen and α-smooth muscle actin also dramatically increased in clipped kidneys, but this effect was blocked by HIF-1α shRNA. In conclusion, long-term overactivation of HIF-1α is a pathogenic factor in chronic renal injury associated with ischemia/hypoxia.

scholarly journals Evaluation of Pathological Association between Stroke-Related QTL and Salt-Induced Renal Injury in Stroke-Prone Spontaneously Hypertensive Rat

2019 ◽  
Vol 2019 ◽  
pp. 1-7
Author(s):  
Mohammad Farhadur Reza ◽  
Davis Ngarashi ◽  
Masamichi Koike ◽  
Masaki Misumi ◽  
Hiroki Ohara ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Genetic Marker ◽  
Renal Injury ◽  
Spontaneously Hypertensive Rat ◽  
Kidney Injury ◽  
Cerebral Stroke ◽  
Chromosome 18 ◽  
Spontaneously Hypertensive ◽  
Congenic Strains ◽  
Hypertensive Rat

The stroke-prone spontaneously hypertensive rat (SHRSP) suffers from severe hypertension and hypertensive organ damage such as cerebral stroke and kidney injury under salt-loading. By a quantitative trait locus (QTL) analysis between SHRSP and SHR (the stroke-resistant parental strain of SHRSP), two major QTLs for stroke susceptibility were identified on chromosomes 1 and 18 of SHRSP, which were confirmed in congenic strains constructed between SHRSP and SHR. As the progression of renal dysfunction was suggested to be one of the key factors inducing stroke in SHRSP, we examined effects of the stroke-related QTLs on kidney injury using two congenic strains harboring either of SHRSP-derived fragments of chromosomes 1 and 18 in the SHR genome. The congenic strains were challenged with 1% NaCl solution for 4 weeks; measurement of systolic blood pressure and urinary isoprostane level (a marker for oxidative stress) and evaluation of renal injury by quantification of genetic marker expression and histological examination were performed. We found that the congenic rats with SHRSP-derived fragment of chromosome 18 showed more severe renal damage with higher expression of Col1α-1 (a genetic marker for renal fibrosis) and higher urinary isoprostane level. In contrast, the fragment of chromosome 1 from SHRSP did not give such effects on SHR. Blood pressure was not greater in either of the congenic strains when compared with SHR. We concluded that the QTL region on chromosome 18 might deteriorate salt-induced renal injury in SHR through a blood pressure-independent mechanism.

scholarly journals Macrophage Phenotype in Kidney Injury and Repair

2015 ◽  
Vol 1 (2) ◽  
pp. 138-146 ◽  
Author(s):  
Xiao-Ming Meng ◽  
Patrick Ming-Kuen Tang ◽  
Jun Li ◽  
Hui Yao Lan
Keyword(s):  
Renal Injury ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Renal Diseases ◽  
Macrophage Phenotype ◽  
M1 Macrophages ◽  
Chronic Kidney Diseases ◽  
Chronic Kidney Injury ◽  
Injury And Repair ◽  
And Function

Background: Glomerular and interstitial macrophage infiltration is a feature for both the acute and chronic kidney diseases. Macrophages have been shown to play a diverse role in kidney injury and repair. Thus, macrophages may be a key cell type in acute and chronic kidney injury and repair. Summary and Key Messages: During renal inflammation, circulating monocytes are recruited and then become activated and polarized. By adapting to the local microenvironment, macrophages can differentiate into different phenotypes and function as a double-bladed sword in different stages of kidney disease. In general, M1 macrophages play a pathogenic role in boosting inflammatory renal injury, whereas M2 macrophages exert an anti-inflammatory and wound healing (or profibrotic) role during renal repair. In this review, we highlight the phenotypic polarization of macrophages in renal diseases and dissect their distinct functions in renal injury and repair processes, respectively. Moreover, the current understanding of regulatory mechanisms on the phenotypic switch and macrophage-related therapy are also intensively discussed.

Blockade of cysteine-rich protein 61 attenuates renal inflammation and fibrosis after ischemic kidney injury

2014 ◽  
Vol 307 (5) ◽  
pp. F581-F592 ◽  
Author(s):  
Chun-Fu Lai ◽  
Shuei-Liong Lin ◽  
Wen-Chih Chiang ◽  
Yung-Ming Chen ◽  
Vin-Cent Wu ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Smooth Muscle Actin ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
Cysteine Rich Protein ◽  
Proximal Tubular

Emerging data have suggested that acute kidney injury (AKI) is often incompletely repaired and can lead to chronic kidney disease (CKD), which is characterized by tubulointerstitial inflammation and fibrosis. However, the underlying mechanisms linking AKI to CKD remain obscure. The present study aimed to investigate the role of cysteine-rich protein 61 (Cyr61) after unilateral kidney ischemia-reperfusion injury (IRI) in mice. After IRI, increased expression of Cyr61 was detected, predominately in the proximal tubular epithelium. This was confirmed by in vitro experiments, which showed that hypoxia stimulated Cyr61 expression in cultured proximal tubular epithelial cells. The proinflammatory property of Cyr61 was indicated by its ability to upregulate monocyte chemoattractant protein-1 and IL-6. Additionally, we found elevated urinary Cyr61 excretion in patients with AKI. Notably, treatment of mice with an anti-Cyr61 antibody attenuated the upregulation of kidney monocyte chemoattractant protein-1, IL-6, IL-1β, and macrophage inflammatory protein-2 and reduced the infiltration of F4/80-positive macrophages on days 7 and 14 after IRI. In addition, blockade of Cyr61 reduced the mRNA expression of collagen, transforming growth factor-β, and plasminogen activator inhibitor-I as well as the degree of collagen fibril accumulation, as evaluated by picrosirius red staining, and levels of α-smooth muscle actin proteins by day 14. Concurrently, in the treated group, peritubular microvascular density was more preserved on day 14. We conclude that Cyr61 blockade inhibits the triad of inflammation, interstitial fibrosis, and capillary rarefaction after severe ischemic AKI. The results of this study expand the knowledge of the mechanisms underlying the AKI-to-CKD transition and suggest that Cyr61 is a potential therapeutic target.

scholarly journals Perivascular CD73+ cells attenuate inflammation and interstitial fibrosis in the kidney microenvironment

2019 ◽  
Vol 317 (3) ◽  
pp. F658-F669 ◽  
Author(s):  
Heather M. Perry ◽  
Nicole Görldt ◽  
Sun-sang J. Sung ◽  
Liping Huang ◽  
Kinga P. Rudnicka ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Purinergic Signaling ◽  
Smooth Muscle Actin ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Perivascular Cells ◽  
Kidney Fibrosis ◽  
Perivascular Cell ◽  
Persistent Inflammation

Progressive tubulointerstitial fibrosis may occur after acute kidney injury due to persistent inflammation. Purinergic signaling by 5′-ectonucleotidase, CD73, an enzyme that converts AMP to adenosine on the extracellular surface, can suppress inflammation. The role of CD73 in progressive kidney fibrosis has not been elucidated. We evaluated the effect of deletion of CD73 from kidney perivascular cells (including pericytes and/or fibroblasts of the Foxd1+ lineage) on fibrosis. Perivascular cell expression of CD73 was necessary to suppress inflammation and prevent kidney fibrosis in Foxd1CreCD73fl/fl mice evaluated 14 days after unilateral ischemia-reperfusion injury or folic acid treatment (250 mg/kg). Kidneys of Foxd1CreCD73fl/fl mice had greater collagen deposition, expression of proinflammatory markers (including various macrophage markers), and platelet-derived growth factor recepetor-β immunoreactivity than CD73fl/fl mice. Kidney dysfunction and fibrosis were rescued by administration of soluble CD73 or by macrophage deletion. Isolated CD73−/− kidney pericytes displayed an activated phenotype (increased proliferation and α-smooth muscle actin mRNA expression) compared with wild-type controls. In conclusion, CD73 in perivascular cells may act to suppress myofibroblast transformation and influence macrophages to promote a wound healing response. These results suggest that the purinergic signaling pathway in the kidney interstitial microenvironment orchestrates perivascular cells and macrophages to suppress inflammation and prevent progressive fibrosis.

Sign in / Sign up

Export Citation Format

Share Document