scholarly journals Fibrosis regression is induced by AdhMMP8 in a murine model of chronic kidney injury

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243307
Author(s):  
Homero Contreras-Salinas ◽  
Alejandra Meza-Rios ◽  
Jesús García-Bañuelos ◽  
Ana Sandoval-Rodriguez ◽  
Laura Sanchez-Orozco ◽  
...  
Keyword(s):  
Serum Creatinine ◽  
Interstitial Fibrosis ◽  
Left Kidney ◽  
Kidney Injury ◽  
Protein Detection ◽  
Experimental Models ◽  
Chronic Injury ◽  
Tubular Atrophy ◽  
Kidney Fibrosis ◽  
Ischemic Period

Adenoviral vector AdhMMP8 (human Metalloproteinase-8 cDNA) administration has been proven beneficial in various experimental models of liver injury improving liver function and decreasing fibrosis. In this study, we evaluated the potential therapeutic AdhMMP8 effect in a chronic kidney damage experimental model. Chronic injury was induced by orogastric adenine administration (100mg/kg/day) to Wistar rats for 4 weeks. AdhMMP8 (3x1011vp/kg) was administrated in renal vein during an induced-ligation-ischemic period to facilitate kidney transduction causing no-additional kidney injury as determined by histology and serum creatinine. Animals were sacrificed at 7- and 14-days post-Ad injection. Fibrosis, histopathological features, serum creatinine (sCr), BUN, and renal mRNA expression of αSMA, Col-1α, TGF-β1, CTGF, BMP7, IL-1, TNFα, VEGF and PAX2 were analyzed. Interestingly, AdhMMP8 administration resulted in cognate human MMP8 protein detection in both kidneys, whereas hMMP8 mRNA was detected only in the left kidney. AdhMMP8 significantly reduced kidney tubule-interstitial fibrosis and glomerulosclerosis. Also, tubular atrophy and interstitial inflammation were clearly decreased rendering improved histopathology, and down regulation of profibrogenic genes expression. Functionally, sCr and BUN were positively modified. The results showed that AdhMMP8 decreased renal fibrosis, suggesting that MMP8 could be a possible therapeutic candidate for kidney fibrosis treatment.

scholarly journals Cellular Mechanisms of Tissue Fibrosis. 3. Novel mechanisms of kidney fibrosis

2013 ◽  
Vol 304 (7) ◽  
pp. C591-C603 ◽  
Author(s):  
Gabriela Campanholle ◽  
Giovanni Ligresti ◽  
Sina A. Gharib ◽  
Jeremy S. Duffield
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Interstitial Fibrosis ◽  
Kidney Injury ◽  
Innate Immune ◽  
Cellular Mechanisms ◽  
Tubular Atrophy ◽  
Kidney Fibrosis ◽  
Capillary Rarefaction ◽  
Peritubular Capillaries

Chronic kidney disease, defined as loss of kidney function for more than three months, is characterized pathologically by glomerulosclerosis, interstitial fibrosis, tubular atrophy, peritubular capillary rarefaction, and inflammation. Recent studies have identified a previously poorly appreciated, yet extensive population of mesenchymal cells, called either pericytes when attached to peritubular capillaries or resident fibroblasts when embedded in matrix, as the progenitors of scar-forming cells known as myofibroblasts. In response to sustained kidney injury, pericytes detach from the vasculature and differentiate into myofibroblasts, a process not only causing fibrosis, but also directly contributing to capillary rarefaction and inflammation. The interrelationship of these three detrimental processes makes myofibroblasts and their pericyte progenitors an attractive target in chronic kidney disease. In this review, we describe current understanding of the mechanisms of pericyte-to-myofibroblast differentiation during chronic kidney disease, draw parallels with disease processes in the glomerulus, and highlight promising new therapeutic strategies that target pericytes or myofibroblasts. In addition, we describe the critical paracrine roles of epithelial, endothelial, and innate immune cells in the fibrogenic process.

P0661DIAGNOSTIC VALUE OF FULL AGE SPECTRUM EQUATION AS A PREDICTOR OF MORPHOLOGICAL LESIONS IN PATIENTS WITH GLOMERULONEPHRITIS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Saganova Elena ◽  
Olga Galkina ◽  
Vasiliy Sipovskii ◽  
Ivan Kayukov, ◽  
Alexei Smirnov
Keyword(s):  
Serum Creatinine ◽  
Interstitial Fibrosis ◽  
Severe Heart Failure ◽  
Kidney Injury ◽  
Roc Curves ◽  
Diagnostic Value ◽  
Tubular Atrophy ◽  
Mild Degree ◽  
Severe Group ◽  
Global Glomerulosclerosis

Abstract Background and Aims Glomerular filtration rate (GFR) is generally accepted as a best overall index of kidney function. However, it remains controversial to choose the optimal equation to estimate GFR in patients with glomerulonephritis (GN). Recent studies have reported that newly developed full age spectrum equation based on normalized serum creatinine (FASsCr) showed improved validity and was less biased, more accurate than currently recommended sCr-based eGFR equations. Our aim was to assess FASsCr equation as a predictor of various morphological lesions in patients with GN. Method 100 patients [48 female, age Me 39 (27; 54) years] with biopsy proven primary GN and without acute kidney injury, infectious diseases, severe heart failure, respiratory insufficiency, cancer were included in the study. Minimal change disease was diagnosed in 9% of cases based on the results of kidney biopsy, in 28% – focal segmental glomerulosclerosis, in 26% – membranous nephropathy and in 37% – IgA-nephropathy. Serum creatinine (sCr) level was measured by enzymatic method (Uni Cel DxC 800 PRO, «Beckman Coulter»,USA). eGFR was calculated using FASsCr equation. The extent of global glomerulosclerosis (GS) was assessed quantitatively as a sum of full and focal sclerotic glomeruli. Tubulo-interstitial fibrosis (TIF) and tubular atrophy (TA) were assessed semi-quantitatively (0-lesions absent; 1-mild focal tubular and interstitial lesions; 2-moderate tubular and interstitial lesions; 3 - diffuse tubular and interstitial lesions). All patients consistently were separated into 2 groups according to the degree of each morphological lesion (GS, TIF or TA): “mild” (GS<25% or TIF/TA grade 0 or 1) and “severe” (GS ≥ than 25% or TIF/TA grade 2-3). Results eGFR using FASsCr equation positively correlated (p<0,001 in all cases) with GS (r=0,44), TIF (r=0,64) and TA (r=0,61) and was significantly higher in patients with “mild” GS, TIF and TA (p<0,001) in comparison with “severe” group. Using ROC-analysis all patients were separated (p<0.001) in 2 groups using FASsCr equation according to the degree of morphological lesions (“mild” or “severe”): GS (Sn – 48.8%, Sp – 88.1%, ACC – 72.0%, AUC – 0.696, cut-off value – 47 ml/min/1.73m2), TIF (Sn - 75.4%, Sp – 76.9%, ACC – 76.0%, AUC – 0.815, cut-off value – 72 ml/min/1.73m2), TA (Sn – 65.9%, Sp – 88.8%, ACC – 70.0%, AUC – 0.798, cut-off value – 74 ml/min/1.73m2), (Figure). Conclusion Our results show that FASsCr equation is a significant marker of various morphological lesions in patients with GN. FASsCr equation predominantly can be used as a predictor of mild degree of interstitial sclerosis and tubular atrophy with high diagnostic value. Figure: ROC curves with 95% CI of BM panel for A – GS; B – TIF; C – TA

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.

FC 044THE LONG-TERM EFFECTS OF ACUTE KIDNEY INJURY ON INTESTINAL OXALATE-DEGRADING BACTERIA IN RATS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Natalia Stepanova ◽  
Ganna Tolstanova ◽  
Valentyn Nepomnyashchii ◽  
Iryna Akulenko ◽  
Svitlana Savchenko ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Serum Creatinine ◽  
Interstitial Fibrosis ◽  
Kidney Injury ◽  
Fecal Microbiota ◽  
Long Term Effects ◽  
Renal Interstitial Fibrosis ◽  
Degrading Bacteria ◽  
Group 1

Abstract Background and Aims Gut microbiota is considered an important factor affecting oxalate handling in the intestine. It has been demonstrated that intestinal oxalate secretion provides a complementary route of excretion, and it becomes more evident when kidney function declines. A diversity of gut oxalate-degrading bacteria (ODB) has been hypothesized to play a role in this process. However, there is a general lack of research on the long-term effects of acute kidney injury (AKI) on ODB and their total oxalate-degrading activity (ODA) in fecal microbiota. In this study, we evaluated whether renal dysfunction could affect intestinal ODB and their total ODA in a rat model of glycerol-induced AKI. Method The Male Wistar rats (200-300 g, n=20) on oxalate-free diet were randomly divided into 2 groups. After 24-h of water deprivation, Group 1 (n=10) received an intramuscular injection of 50% glycerol (10 ml/kg of body weight), and Group 2 (n=10) served as control. The numbers of ODB (incubated in a highly selective Oxalate Medium and determined using culture method) and total fecal ODA were measured after injection on days 7 and 70. The method of redoximetric titration with a KMnO4 solution was adopted to evaluate total ODA in fecal microbiota; the results were expressed as % of oxalate degradation per 0.01 g of feces. Renal injury was assessed by histopathological examination, serum creatinine and daily proteinuria levels after removing the animals from the experiment on day 70. Cortical interstitial fibrosis was measured by computerized image analysis on sections stained with picrosirius red. The median (Me) and the interquartile ranges (Q25; Q75) were calculated and compared using the nonparametric Mann-Whitney test. The Spearman correlation coefficient was used to evaluate association between the examined parameters. Results The obtained results demonstrated: 1) after glycerol injection on day 7, no differences were found in the numbers of ODB and total fecal ODA between the experimental and control groups: 5.9 (5.4-6.0) vs 6.0 (5.4-6.4) CFU/g, p=0.65 and 2.0 (0.1-5.0) vs 2.5 (2.0-9.0) %/0.01g, p=0.24, respectively; 2) after AKI initiation on day 70, the numbers of ODB and total fecal ODA were significantly lower in Group I compared with control Group II (Fig. 1); 3) the higher percentage of renal interstitial fibrosis was, the higher total fecal ODA occurred in the experimental rats (Fig. 2). In addition, the number of ODB in feces in Group 1 had an inverse association with serum creatinine (r=-0.52, p=0.006) and 24-h proteinuria levels (r=-0.86, p&lt;0.0001). Conclusion AKI had the long-term negative effects on the quantitative and qualitative characteristics of ODB in fecal microbiota in rats. Moreover, the results of our study confirmed an increasing trend in total fecal ODA according to the aggravation of renal interstitial fibrosis in rats.

scholarly journals Cisplatin-induced renal toxicity in elderly people

2020 ◽  
Vol 12 ◽  
pp. 175883592092343 ◽  
Author(s):  
ZhiYu Duan ◽  
GuangYan Cai ◽  
JiJun Li ◽  
XiangMei Chen
Keyword(s):  
Elderly Patients ◽  
Elderly People ◽  
Renal Toxicity ◽  
Enzyme Inhibitor ◽  
Interstitial Fibrosis ◽  
Angiotensin Receptor Blockers ◽  
Young Patients ◽  
Kidney Injury ◽  
The Elderly ◽  
Tubular Atrophy

Despite available prevention and treatment measures, such as hydration, diuresis, magnesium supplementation, and amifostine, renal toxicity is still one of the major dose-limiting side effects of cisplatin. The aim of this review is to discuss the issue of cisplatin-induced nephrotoxicity in the elderly. Compared with young patients, the incidences of cisplatin-induced nephrotoxicity and acute kidney injury (AKI) in elderly patients are significantly increased, and survival time may be decreased. Following cisplatin treatment of elderly patients, tubulointerstitial injuries will be significantly aggravated based on their original age, both for acute injuries due to cell necrosis and exfoliation and chronic injuries due to interstitial fibrosis, tubular atrophy, and dilatation. The high incidence of cisplatin-induced nephrotoxicity in elderly patients may be associated with renal hypoperfusion; increased comorbidities, such as chronic kidney disease (CKD), cardiovascular disease, and diabetes mellitus; increased use of combined drugs [especially non-steroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitor and angiotensin receptor blockers (ACEI/ARB), and antibiotics]; decreased clearance of cisplatin; and high plasma ultrafilterable cisplatin. Considering hemodynamic stability and water balance, short duration and low volume hydration may be more suitable for treating elderly people. With the increasing popularity of low-dose daily/weekly regimens, we do not recommend routine diuretic treatment for elderly patients. We recommend using a less nephrotoxic platinum if large doses of cisplatin (100mg/m2) are needed.

scholarly journals Ibrutinib does not prevent kidney fibrosis following acute and chronic injury

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Julie Belliere ◽  
Audrey Casemayou ◽  
Eloïse Colliou ◽  
Hélène El Hachem ◽  
Clément Kounde ◽  
...  
Keyword(s):  
Kidney Injury ◽  
Subsequent Development ◽  
Lymphocytic Leukemia ◽  
Inflammasome Activation ◽  
Chronic Injury ◽  
Kidney Fibrosis ◽  
Nlrp3 Inflammasome Activation ◽  
Candidate Drug ◽  
Btk Inhibitor

AbstractRecent studies suggested that ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, developed for the treatment of chronic lymphocytic leukemia, may prevent NLRP3 inflammasome activation in macrophages, IL-1β secretion and subsequent development of inflammation and organ fibrosis. The role of NLRP3 has been underlined in the various causes of acute kidney injury (AKI), a pathology characterized by high morbimortality and risk of transition toward chronic kidney disease (CKD). We therefore hypothesized that the BTK-inhibitor ibrutinib could be a candidate drug for AKI treatment. Here, we observed in both an AKI model (glycerol-induced rhabdomyolysis) and a model of rapidly progressive kidney fibrosis (unilateral ureteral obstruction), that ibrutinib did not prevent inflammatory cell recruitment in the kidney and fibrosis. Moreover, ibrutinib pre-exposure led to high mortality rate owing to severer rhabdomyolysis and AKI. In vitro, ibrutinib potentiated or had no effect on the secretion of IL-1β by monocytes exposed to uromodulin or myoglobin, two danger-associated molecule patterns proteins involved in the AKI to CKD transition. According to these results, ibrutinib should not be considered a candidate drug for patients developing AKI.

scholarly journals Lithium Nephrotoxicity

2000 ◽  
Vol 11 (8) ◽  
pp. 1439-1448 ◽  
Author(s):  
GLEN S. MARKOWITZ ◽  
JAI RADHAKRISHNAN ◽  
NEERAJA KAMBHAM ◽  
ANTHONY M. VALERI ◽  
WILLIAM H. HINES ◽  
...  
Keyword(s):  
Serum Creatinine ◽  
Focal Segmental Glomerulosclerosis ◽  
Interstitial Fibrosis ◽  
Renal Cysts ◽  
Significant Degree ◽  
Fisher Exact Test ◽  
Tubular Atrophy ◽  
Segmental Glomerulosclerosis ◽  
Tubulointerstitial Nephropathy ◽  
Collecting Tubules

Abstract. This study examines the clinical features, pathologic findings, and outcome of 24 patients with biopsy-proven lithium toxicity. The patient population was 50% male, 87.5% Caucasian, and had a mean age of 42.5 yr (range, 26 to 57). Mean duration of lithium therapy for bipolar disorder was 13.6 yr (range, 2 to 25). All patients were biopsied for renal insufficiency (mean serum creatinine 2.8 mg/dl; range, 1.3 to 8.0), with associated proteinuria >1.0 g/d in 41.7%. Nephrotic proteinuria (>3.0 g/d) was present in 25%. Other features included nephrogenic diabetes insipidus in 87% and hypertension in 33.3%. Renal biopsy revealed a chronic tubulointerstitial nephropathy in 100%, with associated cortical and medullary tubular cysts (62.5%) or dilatation (33.3%). All of the renal cysts stained for epithelial membrane antigen, while 51.4% stained with lectin Arachis hypogaea, and only 3.8% stained with Tetragonolobus purpureas, indicating they originated from distal and collecting tubules. The degree of tubular atrophy and interstitial fibrosis was graded as severe in 58.3%, moderate in 37.5%, and mild in 4.2% of cases. There was a surprisingly high prevalence of focal segmental glomerulosclerosis (50%) and global glomerulosclerosis (100%), sometimes of equivalent severity to the chronic tubulointerstitial disease. The significant degree of foot process effacement (mean 34%, five of 14 cases with >50%) suggests a potential direct glomerular toxicity. Focal segmental glomerulosclerosis correlated with proteinuria >1.0 g/d (P= 0.0014, Fisher exact test). Despite discontinuation of lithium, seven of nine patients with initial serum creatinine values >2.5 mg/dl progressed to end-stage renal disease (ESRD). Only three patients, all with initial serum creatinine <2.1 mg/dl, had subsequent improvement in renal function. By Kaplan-Meier survival analysis, the only significant predictor of progression to ESRD was serum creatinine >2.5 mg/dl at biopsy (P= 0.008). In conclusion, lithium nephrotoxicity primarily targets distal and collecting tubules, with a higher incidence of proteinuria and associated glomerular pathology than recognized previously. Renal dysfunction is often irreversible despite lithium withdrawal, and early detection is essential to prevent progression to ESRD.

scholarly journals Sex and kidney ACE2 expression in primary focal segmental glomerulosclerosis: A NEPTUNE study

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252758
Author(s):  
Nicholas A. Maksimowski ◽  
James W. Scholey ◽  
Vanessa R. Williams ◽  
Keyword(s):  
Kidney Disease ◽  
Focal Segmental Glomerulosclerosis ◽  
Current Knowledge ◽  
Interstitial Fibrosis ◽  
Linear Regression Analysis ◽  
Renin Angiotensin System ◽  
Multiple Linear Regression Analysis ◽  
Tubular Atrophy ◽  
Kidney Fibrosis ◽  
Segmental Glomerulosclerosis

Background Angiotensin-converting enzyme 2 (ACE2) has been implicated in the pathogenesis of experimental kidney disease. ACE2 is on the X chromosome, and in mice, deletion of ACE2 leads to the development of focal segmental glomerulosclerosis (FSGS). The relationship between sex and renal ACE2 expression in humans with kidney disease is a gap in current knowledge. Methods We studied renal tubulointerstitial microarray data and clinical variables from subjects with FSGS enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) study. We compared relationships between ACE2 expression and age, estimated glomerular filtration rate (eGFR), urinary albumin to creatinine ratio (UACR), interstitial fibrosis, tubular atrophy, and genes implicated in inflammation and fibrosis in male and female subjects. Results ACE2 mRNA expression was lower in the tubulointerstitium of males compared to females (P = 0.0026). Multiple linear regression analysis showed that ACE2 expression was related to sex and eGFR but not to age or treatment with renin angiotensin system blockade. ACE2 expression is also related to interstitial fibrosis, and tubular atrophy, in males but not in females. Genes involved in inflammation (CCL2 and TNF) correlated with ACE2 expression in males (TNF: r = -0.65, P < 0.0001; CCL2: r = -0.60, P < 0.0001) but not in females. TGFB1, a gene implicated in fibrosis correlated with ACE2 in both sexes. Conclusions Sex is an important determinant of ACE2 expression in the tubulointerstitium of the kidney in FSGS. Sex also influences the relationships between ACE2, kidney fibrosis, and expression of genes involved in kidney inflammation.

scholarly journals Comparative Histological Subtyping of Immune Cell Infiltrates in MPO-ANCA and PR3-ANCA Glomerulonephritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Samy Hakroush ◽  
Désirée Tampe ◽  
Philipp Ströbel ◽  
Peter Korsten ◽  
Björn Tampe
Keyword(s):  
Mononuclear Cell ◽  
Plasma Cells ◽  
Immune Cell ◽  
Interstitial Fibrosis ◽  
Kidney Injury ◽  
Tubular Atrophy ◽  
Interstitial Inflammation ◽  
Tubulointerstitial Lesions ◽  
Mononuclear Cell Infiltrates ◽  
Immune Cell Infiltrates

BackgroundAcute kidney injury (AKI) is a common and severe complication of anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), potentially leading to chronic kidney disease (CKD), end-stage renal disease (ESRD), or death. Pathogenic ANCAs, in particular proteinase 3 (PR3) and myeloperoxidase (MPO), trigger a deleterious immune response with intrarenal immune cell infiltration resulting in a pauci-immune necrotizing and crescentic glomerulonephritis (GN). However, a systematic analysis of intrarenal immune cell subtypes concerning neutrophils, eosinophils, plasma cells, and mononuclear cell infiltrates (macrophages, lymphocytes) in ANCA GN remains elusive. Therefore, we aimed to compare distinct immune cell infiltrates in association with clinicopathological findings in ANCA GN.MethodsA total of 53 kidney biopsies with ANCA GN at the University Medical Center Göttingen were retrospectively analyzed. Histological infiltrates of neutrophils, eosinophils, plasma cells, and mononucleated cells (macrophages, lymphocytes) were quantified as a fraction of the total area of inflammation.ResultsNeutrophilic infiltrates were associated with glomerular necrosis and severe kidney injury in ANCA GN. Among tubulointerstitial lesions, intrarenal neutrophils correlated with interstitial inflammation, tubulitis, and inflammation in areas of interstitial fibrosis/tubular atrophy (IFTA), representing active inflammatory lesions. Concerning eosinophils, infiltrates were associated with severe kidney injury, interstitial inflammation, and cellular casts independent of glomerular lesions, implicating a distinct role in inflammation and damage in ANCA GN. Plasma cell infiltrates correlated with tubulitis and interstitial fibrosis and were associated with renal replacement therapy during the short-term disease course. Finally, mononuclear cell infiltrates correlated with severe kidney injury and active histopathological lesions (glomerular crescents, interstitial inflammation, tubulitis, inflammation, and tubulitis in areas of IFTA) besides chronic lesions (interstitial fibrosis and tubular atrophy) in ANCA GN. Interestingly, intrarenal subtypes of immune cell infiltrates differed in MPO-ANCA versus PR3-ANCA GN and were associated with distinct glomerular and tubulointerstitial lesions, implicating different pathogenic mechanisms of kidney injury in ANCA subtypes.ConclusionOur observations imply distinct pathomechanisms contributing to inflammation and renal injury in MPO vs. PR3-associated ANCA GN and potentially contribute to new therapeutic targets in specific ANCA subtypes.

scholarly journals Nicotinamide Mononucleotide Attenuates Renal Interstitial Fibrosis After AKI by Suppressing Tubular DNA Damage and Senescence

2021 ◽  
Vol 12 ◽  
Author(s):  
Yan Jia ◽  
Xin Kang ◽  
Lishan Tan ◽  
Yifei Ren ◽  
Lei Qu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Recovery Phase ◽  
Tubular Cell ◽  
Dna Damage And Repair ◽  
Kidney Fibrosis ◽  
Beneficial Effects

Acute kidney injury (AKI) is a worldwide health problem currently lacking therapeutics that directly promote renal repair or prevent the occurrence of chronic fibrosis. DNA damage is a feature of many forms of kidney injury, and targeting DNA damage and repair might be effective strategies for kidney protection in AKI. Boosting nicotinamide adenine dinucleotide (NAD+) levels is thought to have beneficial effects on DNA damage repair and fibrosis in other organs. However, no kidney-related studies of such effects have been performed to date. Here, we have shown that NMN (an NAD+ precursor) administration could significantly reduce tubular cell DNA damage and subsequent cellular senescence induced by hydrogen peroxide and hypoxia in human proximal tubular cells (HK-2 cells). The DNA damage inhibition, antiaging and anti-inflammatory effects of NMN were further confirmed in a unilateral ischemia-reperfusion injury (uIRI) mouse model. Most importantly, the antifibrosis activity of NMN was also shown in ischemic AKI mouse models, regardless of whether NMN was administered in advance or during the recovery phase. Collectively, these results suggest that NMN could significantly inhibit tubular cell DNA damage, senescence and inflammation. NMN administration might be an effective strategy for preventing or treating kidney fibrosis after AKI.

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