Silencing of SOCS‐1 and SOCS‐3 suppresses renal interstitial fibrosis by alleviating renal tubular damage in a rat model of hydronephrosis

OBJECTIVES/GOALS: Tubulointerstitial damage in lupus nephritis (LN) is a strong predictor of progression to chronic kidney disease and end stage renal disease (ESRD). While complement activation mediates glomerular injury, the role of complement in renal tubular damage has not been evaluated. We investigated the association between complement activation and tubulointerstitial fibrosis. METHODS/STUDY POPULATION: Patients with LN were selected randomly between July 2014 - July 2016. Chromogenic immunohistochemistry was performed on formalin-fixed, paraffin-embedded, 4-µm human renal biopsy sections using unconjugated, murine anti-human Complement C9 (Hycult Biotech, clone X197) as a marker of the terminal complement activation. Positive control is C3 glomerulopathy and negative control is normal kidney. Tubular basement membrane C9 staining intensity were analyzed on semiquantitative scale 0 to 3 by a renal pathologist. Interstitial fibrosis/tubular atrophy were categorized into low (0–10%), medium (11–20%), or high (≥21%). Clinical parameters were assessed at time of biopsy and 6 months post biopsy. Bivariate associations were assessed between presence of tubular C9 (C9+) and other covariates. RESULTS/ANTICIPATED RESULTS: Renal biopsies from 30 LN studied, 23 (77%) of which had proliferative LN. There were 24 (80%) women, mean (SD) age 33 (12) years. Positive tubular C9 staining was observed in 7/30 (23%) biopsies. At time of renal biopsy, C9+ patients had significantly higher urine protein, compared to C9- patients: median (IQR) 6.2g (3.3-13.1) vs. 2.4g (1.3-4.6), p<0.01. The differences persisted at 6 months after induction therapy: 1.08g (1.0-8.3) in C9+ vs. 0.68g (0.2-2.1) in C9- patients, p = 0.06. There was no significant difference in creatinine at renal biopsy between the two groups. Tubular C9 deposition was associated with interstitial fibrosis: 49% had severe interstitial fibrosis vs. none in the C9- group, p = <0.01. Higher proportion of C9+ patients had moderate NIH Chronicity index: 42.9% vs 8.7% in the C9- group, p = 0.07. DISCUSSION/SIGNIFICANCE OF IMPACT: Tubular C9 deposition is significantly associated with proteinuria, interstitial fibrosis and increased chronicity which predict progression to ESRD and high mortality. This finding suggests that complement activation in the tubules may be linked to proteinuria and contribute to mechanism in tubulointerstitial damage in LN.

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Aggravated renal tubular damage and interstitial fibrosis in mice lacking guanylyl cyclase-A (GC-A), a receptor for atrial and B-type natriuretic peptides

Clinical and Experimental Nephrology ◽

10.1007/s10157-014-0982-1 ◽

2014 ◽

Vol 19 (2) ◽

pp. 197-207 ◽

Cited By ~ 4

Author(s):

Fumiki Yoshihara ◽

Takeshi Tokudome ◽

Ichiro Kishimoto ◽

Kentaro Otani ◽

Atsunori Kuwabara ◽

...

Keyword(s):

Guanylyl Cyclase ◽

Natriuretic Peptides ◽

Interstitial Fibrosis ◽

Tubular Damage ◽

Renal Tubular Damage ◽

Renal Tubular

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Fractional excretion of magnesium as an early indicator of renal tubular damage in normotensive diabetic nephropathy

Turkish Journal of Biochemistry ◽

10.1515/tjb-2019-0232 ◽

2020 ◽

Vol 45 (5) ◽

pp. 543-551

Author(s):

Fatih Ozcelik ◽

Serif Kactas ◽

Halime Hanim Pence ◽

Saadet Kurcenli ◽

Erdim Sertoglu ◽

...

Keyword(s):

Fractional Excretion ◽

Study Patient ◽

Control Group ◽

Tubular Damage ◽

Renal Tubular Damage ◽

Renal Tubular ◽

Excretion Rates ◽

Urine And Serum ◽

Diagnostic And Prognostic Value

AbstractObjectivesThe aim of the present study is to evaluate the diagnostic powers of fractional magnesium, sodium and potassium as markers of renal tubular damage in normotensive type 2 diabetes mellitus (T2DM) patients with respect to microalbuminuria and estimated glomerular filtration rate (eGFR).Materials and methodsForty healthy volunteers and 91 normotensive T2DM patients were included in the study. Patient group was divided into two according to albuminuria level; 49 were normoalbuminuric and 42 were microalbuminuric. In addition to albumin in urine, urine and serum Na, K, Mg and creatinine values were measured to calculate fractional electrolyte excretion rates.ResultsIn normoalbuminuric and microalbuminuric groups, fractional excretion of magnesium (FEMg) values were found to be significantly higher than the control group (p < 0.05). There was a moderate correlation between FEMg and albümin to cratinin ratio (ACR) (Spearman r = 0.3215, p < 0.05). In the ROC analysis for eGFR and FEMg based on microalbuminuria, the areas under the curve were 0.625 and 0.732, respectively (diagnostic sensitivity 59.52% and 66.67%; specificity 70.79% and 77.53%, p < 0.05).ConclusionFor renal tubular damage predicted by microalbuminuria, FEMg could be accepted as a candidate biochemical marker with diagnostic and prognostic value.

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LRG1 Mitigates Renal Interstitial Fibrosis through Alleviating Capillary Rarefaction and Inhibiting Inflammatory and Pro-Fibrotic Cytokines

American Journal of Nephrology ◽

10.1159/000514167 ◽

2021 ◽

pp. 1-11

Author(s):

Ting-Ting Liu ◽

Ran Luo ◽

Yi Yang ◽

Yi-Chun Cheng ◽

Dan Chang ◽

...

Keyword(s):

Renal Fibrosis ◽

Interstitial Fibrosis ◽

Critical Role ◽

Tube Formation ◽

Renal Interstitial Fibrosis ◽

Genetic Ablation ◽

Capillary Rarefaction ◽

Peritubular Capillaries ◽

Renal Tubular

Introduction: Increasing evidence has demonstrated that loss of peritubular capillaries plays a critical role in renal interstitial fibrosis. Leucine-rich α2-glycoprotein-1 (LRG1) has been observed promoting angiogenesis in the ocular disease mouse model and myocardial infarction model. We aimed to explore the role of LRG1 in renal interstitial fibrosis. Methods: We analyzed the expression of LRG1 in the plasma and kidney of CKD patients by ELISA and immunohistochemistry. Relationships between the expression of LRG1 in plasma and kidney and renal fibrosis and inflammation were analyzed. Tube formation assay was used to detect the angiogenesis in the human umbilical vein endothelial cell lines (HUVECs). And real-time PCR was used to detect the mRNA expression of LRG1, inflammatory factors, renal tubular injury indicators, pro-fibrotic cytokines, and CD31. We examined the effects of genetic ablation of LRG1 on renal fibrosis induced by unilateral ureteral obstruction (UUO) mice model at day 7. Results: We demonstrated that the expression of LRG1 in renal tissues and plasma samples was upregulated in CKD patients. And the expression of LRG1 was elevated in human renal tubular epithelial cell line (HK-2) cells in response to the stimulation of TNF-α in vitro, and in kidney after UUO in vivo. The deficiency of the LRG1 gene aggravated renal fibrosis, inflammatory cells infiltration, and capillary rarefaction after UUO. In vitro, LRG1 promoted the tube formation of HUVEC cells. LRG1 inhibits fibronectin secretion induced by TGF-β1 in HK-2 and overexpression of LRG1 in HK-2 cells decreased fibronectin secretion. Conclusion: LRG1 may prevent renal fibrosis by inhibiting the secretion of inflammatory and pro-fibrotic cytokines and promoting angiogenesis.

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Tactical approaxhes to diagnosis and treatment of hepatorenal syndrome in patients with blastomatous obstructive jaundice

Problems of Uninterrupted Medical Training and Science ◽

10.31071/promedosvity2021.02.028 ◽

2021 ◽

Vol 42 (2) ◽

pp. 28-31

Author(s):

S. V. Kosulin ◽

◽

Ju. O. Vinnik ◽

Ju. V. Ivanova ◽

◽

...

Keyword(s):

Obstructive Jaundice ◽

Hepatorenal Syndrome ◽

Resistance Index ◽

Doppler Imaging ◽

Coagulation System ◽

Tubular Damage ◽

Renal Tubular Damage ◽

Renal Tubular ◽

Neutrophil Gelatinase

The article discusses problems of early diagnosis and, accordingly, treatment of hepatorenal syndrome (HRS) in case of obstructive jaundice of blastomatous origin. The results of a comprehensive examination of 37 patients with blastomatous obstructive jaundice (OJ) with clinical and laboratory signs of HRS were analyzed. Patients were evaluated for clinical and biochemical parameters of blood and urine, blood electrolytes, indicators of the blood coagulation system according to unified methods. The main work is devoted to the determination of the biomarker of renal tubular damage, neutrophil-gelatinase-associated lipocaine (s-NGAL) as a marker and indicator of HRS severity, careful and detailed analysis, monitoring of levels (s-NGAL) and other bioactive substances as an indicator of treatment efficacy. Introduction of active ultrasound as a replacement for contrast computer tomography to reduce the load on precompromised kidneys. It has been proven that the level of renal tubular damage, neutrophil-gelatinase-associated lipocaine s-NGAL is an early marker of renal damage whose function is to reduce the severity of damage to the proximal tubules of the kidneys, normalize damaged tissue by participating in apoptosis, increase survival of damaged restoration of damaged epithelium, stimulation of differentiation and structural reorganization of renal epithelial cells. The fact that s-NGAL was not significantly reduced in the stage of recovery of diuresis, confirms the presence of patients with blastomatous MF severe and persistent toxic tubulointerstitial disorders. Based on this determination of the biomarker (s-NGAL) in the serum of patients with blastomatous mechanical jaundice and performing in them at primary ultrasound color Doppler mapping and pulsed wave Doppler imaging of the kidneys with the calculation of the resistance index may serve as early signs of damage.

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Chronic Renal Tubular Damage Caused by Cyclosporin A

Nephrotoxicity ◽

10.1007/978-1-4757-2040-2_46 ◽

1989 ◽

pp. 309-314

Author(s):

P. H. Whiting ◽

N. J. Saunders ◽

K. J. Thomson ◽

J. G. Simpson

Keyword(s):

Cyclosporin A ◽

Tubular Damage ◽

Renal Tubular Damage ◽

Renal Tubular

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Dihydromyricetin promotes autophagy and attenuates renal interstitial fibrosis by regulating miR-155-5p/PTEN signaling in diabetic nephropathy

Bosnian Journal of Basic Medical Sciences ◽

10.17305/bjbms.2019.4410 ◽

2019 ◽

Author(s):

Liming Guo ◽

Kuibi Tan ◽

Qun Luo ◽

Xu Bai

Keyword(s):

Diabetic Nephropathy ◽

Signaling Pathway ◽

Rat Model ◽

Interstitial Fibrosis ◽

Mtor Signaling ◽

Luciferase Assay ◽

Luciferase Reporter ◽

Mtor Signaling Pathway ◽

Renal Interstitial Fibrosis ◽

Gene Assay

Diabetic nephropathy (DN) is the most common complication of diabetes and is prone to kidney failure. Dihydromyricetin (DHM) has been reported to have a variety of pharmacological activities. This study aims to explore the effect of DHM on DN and the underlying molecular mechanism. An in vivo DN rat model was established. The degree of renal interstitial fibrosis (RIF) was detected by hematoxylin-eosin (HE) staining, Masson's trichrome staining, and immunohistochemistry (IHC). In vitro, NRK-52E cells were divided into four groups: normal glucose (NG), high glucose (HG), HG+DHM, and HG+rapamycin (autophagy inhibitor). The levels of autophagy- and fibrosis-related proteins were analyzed by western blotting. The expression of miR-155-5p and phosphatase and tensin homolog deleted on chromosome ten (PTEN) and their relationship were assessed by quantitative reverse transcription (qRT)-PCR and dual luciferase reporter gene assay. Our results showed that RIF was increased in DN rat model and in HG-induced NRK-52E cells. DHM treatment attenuated the increased RIF and also increased autophagy. MiR-155-5p expression was increased, while PTEN expression was decreased in DN rat and cell model, and DHM reversed both effects. Dual luciferase assay showed that PTEN was the target gene of miR-155-5p. DHM inhibited HG-induced fibrosis and promoted autophagy by inhibiting miR-155-5p expression in NRK-52E cells. In addition, DHM promoted autophagy by inhibiting the PI3K/AKT/mTOR signaling pathway. In conclusion, DHM promotes autophagy and attenuates RIF by regulating the miR-155-5p/PTEN signaling and PI3K/AKT/mTOR signaling pathway in DN.

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Soluble receptor for advanced glycation end products protects from ischemia- and reperfusion-induced acute kidney injury

Biology Open ◽

10.1242/bio.058852 ◽

2021 ◽

Author(s):

Taro Miyagawa ◽

Yasunori Iwata ◽

Megumi Oshima ◽

Hisayuki Ogura ◽

Koichi Sato ◽

...

Keyword(s):

Acute Kidney Injury ◽

Advanced Glycation End Products ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Tubular Damage ◽

Advanced Glycation ◽

Renal Tubular Damage ◽

Glycation End Products ◽

End Products ◽

Renal Tubular

The full-length receptor for advanced glycation end products (RAGE) is a multiligand pattern recognition receptor. High-mobility group box 1 (HMGB1) is a RAGE ligand of damage-associated molecular patterns that elicits inflammatory reactions. The shedded isoform of RAGE and endogenous secretory RAGE (esRAGE), a splice variant, are soluble isoforms (sRAGE) that act as organ-protective decoys. However, the pathophysiologic roles of RAGE/sRAGE in acute kidney injury (AKI) remain unclear. We found that AKI was more severe, with enhanced renal tubular damage, macrophage infiltration, and fibrosis, in mice lacking both RAGE and sRAGE than in wild-type control mice. Using murine tubular epithelial cells (TECs), we demonstrated that hypoxia upregulated messenger RNA (mRNA) expression of HMGB1 and tumor necrosis factor α (TNF-α), whereas RAGE and esRAGE expressions were paradoxically decreased. Moreover, the addition of recombinant sRAGE canceled hypoxia-induced inflammation and promoted cell viability in cultured TECs. sRAGE administration prevented renal tubular damage in models of ischemia/reperfusion-induced AKI and of anti-glomerular basement membrane (anti-GBM) glomerulonephritis. These results suggest that sRAGE is a novel therapeutic option for AKI.

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