scholarly journals TRPV1 Hyperfunction Involved in Uremic Toxin Indoxyl Sulfate-Mediated Renal Tubular Damage

2020 ◽  
Vol 21 (17) ◽  
pp. 6212 ◽  
Author(s):  
Chien-Lin Lu ◽  
Chun-Hou Liao ◽  
Kuo-Cheng Lu ◽  
Ming-Chieh Ma
Keyword(s):  
Transient Receptor Potential ◽  
Mdck Cells ◽  
Indoxyl Sulfate ◽  
Transient Receptor Potential Vanilloid ◽  
Tubular Damage ◽  
Uremic Toxin ◽  
Dependent Manner ◽  
Renal Tubular Damage ◽  
Tubular Cells ◽  
Renal Tubular

Indoxyl sulfate (IS) is accumulated during severe renal insufficiency and known for its nephrotoxic properties. Transient receptor potential vanilloid 1 (TRPV1) is present in the kidney and acts as a renal sensor. However, the mechanism underlying IS-mediated renal tubular damage in view of TRPV1 is lacking. Here, we demonstrated that TRPV1 was expressed in tubular cells of Lilly Laboratories cell-porcine kidney 1 (LLC-PK1) and Madin-Darby canine kidney cells (MDCK). IS treatment in both cells exhibited tubular damage with increased LDH release and reduced cell viability in dose- and time-dependent manners. MDCK, however, was more vulnerable to IS. We, therefore, investigated MDCK cells to explore a more detailed mechanism. Interestingly, IS-induced tubular damage was markedly attenuated in the presence of selective TRPV1 blockers. IS showed no effect on TRPV1 expression but significantly increased arachidonate 12-lipoxygenase (ALOX12) protein, mRNA expression, and 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) amounts in a dose-dependent manner, indicating that the ALOX12/12(S)-HETE pathway induced TRPV1 hyperfunction in IS-mediated tubulotoxicity. Blockade of ALOX12 by cinnamyl-3,4-dihydroxy-α-cyanocinnamate or baicalein attenuated the effects of IS. Since aryl hydrocarbon receptor (AhR) activation after IS binding is crucial in mediating cell death, here, we found that the AhR blockade not only ameliorated tubular damage but also attenuated ALOX12 expression and 12(S)-HETE production caused by IS. The uremic toxic adsorbent AST-120, however, showed little effect on ALOX12 and 12(S)-HETE, as well as IS-induced cell damage. These results clearly indicated that IS activated AhR and then upregulated ALOX12, and this induced endovanilloid 12(S)-HETE synthesis and contributed to TRPV1 hyperfunction in IS-treated tubular cells. Further study on TRPV1 may attenuate kidney susceptibility to the functional loss of end-stage kidney disease via IS.

scholarly journals TRPV1 Hyperfunction Contributes to Renal Inflammation in Oxalate Nephropathy

2021 ◽  
Vol 22 (12) ◽  
pp. 6204
Author(s):  
Chien-Lin Lu ◽  
Te-Yi Teng ◽  
Min-Tser Liao ◽  
Ming-Chieh Ma
Keyword(s):  
Oxidative Stress ◽  
Transient Receptor Potential ◽  
Cell Damage ◽  
Transient Receptor Potential Vanilloid ◽  
Tubular Damage ◽  
Dependent Manner ◽  
Crystal Deposition ◽  
Renal Inflammation ◽  
Urinary Supersaturation ◽  
Oxalate Nephropathy

Inflammation worsens oxalate nephropathy by exacerbating tubular damage. The transient receptor potential vanilloid 1 (TRPV1) channel is present in kidney and has a polymodal sensing ability. Here, we tested whether TRPV1 plays a role in hyperoxaluria-induced renal inflammation. In TRPV1-expressed proximal tubular cells LLC-PK1, oxalate could induce cell damage in a time- and dose-dependent manner; this was associated with increased arachidonate 12-lipoxygenase (ALOX12) expression and synthesis of endovanilloid 12(S)-hydroxyeicosatetraenoic acid for TRPV1 activation. Inhibition of ALOX12 or TRPV1 attenuated oxalate-mediated cell damage. We further showed that increases in intracellular Ca2+ and protein kinase C α activation are downstream of TRPV1 for NADPH oxidase 4 upregulation and reactive oxygen species formation. These trigger tubular cell inflammation via increased NLR family pyrin domain-containing 3 expression, caspase-1 activation, and interleukin (IL)-1β release, and were alleviated by TRPV1 inhibition. Male hyperoxaluric rats demonstrated urinary supersaturation, tubular damage, and oxidative stress in a time-dependent manner. Chronic TRPV1 inhibition did not affect hyperoxaluria and urinary supersaturation, but markedly reduced tubular damage and calcium oxalate crystal deposition by lowering oxidative stress and inflammatory signaling. Taking all these results together, we conclude that TRPV1 hyperfunction contributes to oxalate-induced renal inflammation. Blunting TRPV1 function attenuates hyperoxaluric nephropathy.

scholarly journals Increased vascular permeability and severe renal tubular damage after ischemia-reperfusion injury in mice lacking adiponectin or T-cadherin

2020 ◽  
Author(s):  
Yuri Tsugawa-Shimizu ◽  
Yuya Fujishima ◽  
Shunbun Kita ◽  
Satoshi Minami ◽  
Taka-aki Sakaue ◽  
...  
Keyword(s):  
Vascular Permeability ◽  
Ischemia Reperfusion Injury ◽  
Kidney Diseases ◽  
Ischemia Reperfusion ◽  
Tubular Damage ◽  
Dependent Manner ◽  
Wild Type ◽  
Renal Tubular Damage ◽  
Peritubular Capillaries ◽  
Renal Tubular

Adiponectin (APN) is a circulating protein specifically produced by adipocytes. Native APN specifically binds to T-cadherin, a glycosylphosphatidylinositol-anchored protein, mediating the exosome-stimulating effects of APN in endothelial, muscle, and mesenchymal stem cells. It was previously reported that APN has beneficial effects on kidney diseases, but the role of T-cadherin has not been clarified yet. Here, our immunofluorescence study indicated the existence of both T-cadherin and APN protein in pericytes, subsets of tissue-resident mesenchymal stem/progenitor cells positive for PDGFRβ, surrounding peritubular capillaries. In an acute renal ischemia-reperfusion (I/R) model, T-cadherin-KO mice, similar to APN-KO mice, exhibited the more progressive phenotype of renal tubular damage and increased vascular permeability than wild-type mice. In addition, in response to I/R injury, the renal PDGFRβ-positive cell area increased in wild-type mice, but opposingly decreased both in Tcad-KO and APN-KO mice, suggesting severe pericyte loss. Mouse primary pericytes also expressed T-cadherin. APN promoted exosome secretion in a T-cadherin-dependent manner. Such exosome production from pericytes may play an important role in maintaining the capillary network and APN-mediated inhibition of renal tubular injury. In summary, our study suggested that APN protected the kidney in an acute renal injury model by binding to T-cadherin.

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

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.

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

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.

Chronic Renal Tubular Damage Caused by Cyclosporin A

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

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

2017 ◽  
Vol 119 (2) ◽  
pp. 2200-2211 ◽  
Author(s):  
Gui‐Hong Zheng ◽  
Yong‐Jian Wang ◽  
Xin Wen ◽  
Xin‐Rui Han ◽  
Min Shen ◽  
...  
Keyword(s):  
Rat Model ◽  
Interstitial Fibrosis ◽  
Tubular Damage ◽  
Renal Interstitial Fibrosis ◽  
Renal Tubular Damage ◽  
Renal Tubular

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

Biology Open ◽  
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.

scholarly journals HIF-1-mediated production of exosomes during hypoxia is protective in renal tubular cells

2017 ◽  
Vol 313 (4) ◽  
pp. F906-F913 ◽  
Author(s):  
Wei Zhang ◽  
Xiangjun Zhou ◽  
Qisheng Yao ◽  
Yutao Liu ◽  
Hao Zhang ◽  
...  
Keyword(s):  
Cell Injury ◽  
Hypoxia Inducible Factor ◽  
Atp Depletion ◽  
Tubular Cell ◽  
Renal Tubular Cell ◽  
Dependent Manner ◽  
Protective Effects ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

Exosomes are nano-sized vesicles produced and secreted by cells to mediate intercellular communication. The production and function of exosomes in kidney tissues and cells remain largely unclear. Hypoxia is a common pathophysiological condition in kidneys. This study was designed to characterize exosome production during hypoxia of rat renal proximal tubular cells (RPTCs), investigate the regulation by hypoxia-inducible factor-1 (HIF-1), and determine the effect of the exosomes on ATP-depletion-induced tubular cell injury. Hypoxia did not change the average sizes of exosomes secreted by RPTCs, but it significantly increased exosome production in a time-dependent manner. HIF-1 induction with dimethyloxalylglycine also promoted exosome secretion, whereas pharmacological and genetic suppression of HIF-1 abrogated the increase of exosome secretion under hypoxia. The exosomes from hypoxic RPTCs had inhibitory effects on apoptosis of RPTCs following ATP depletion. The protective effects were lost in the exosomes from HIF-1α knockdown cells. It is concluded that hypoxia stimulates exosome production and secretion in renal tubular cells. The exosomes from hypoxic cells are protective against renal tubular cell injury. HIF-1 mediates exosome production during hypoxia and contributes to the cytoprotective effect of the exosomes.

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