Tubular Injury and Dendritic Cell Activation Are Integral Components of Light Chain–Associated Acute Tubulointerstitial Nephritis

Context.— Light chain–associated acute tubulointerstitial nephritis (LC-ATIN) is a variant of light chain proximal tubulopathy (LCPT). It is characterized by interstitial inflammation with tubulitis and deposition of monoclonal light chains in the tubulointerstitium. LC-ATIN is a rather poorly recognized pattern of LCPT and not much is known about this entity. Objective.— To determine the clinicopathologic features of patients with LC-ATIN and investigate the proximal tubular injury and mechanism of interstitial inflammation in LC-ATIN. Design.— A total of 38 cases of LC-ATIN were identified from the archives of 5043 renal biopsy specimens. In all cases, routine light microscopic examination, immunofluorescence, and electron microscopic examination were performed. In selected cases, immunofluorescent staining of dendritic cells and immunohistochemical staining for 4 tubular injury markers—KIM-1, p53, bcl-2, and Ki-67—were performed. Results.— A characteristic finding in LC-ATIN cases was immunofluorescence staining of monoclonal light chains along tubular basement membranes in linear fashion and inside proximal tubular cells with a granular pattern. No monoclonal light chains were present in glomerular or vascular compartments confirmed with immunofluorescence, electron microscopy, and ultrastructural gold labeling. Ten of 15 LC-ATIN cases (67%) were concurrently positive for the 4 tubular injury markers. Dendritic cells were identified within the tubulointerstitium in the renal biopsy specimens, interacting with surrounding tubules with light-chain deposits and inflammatory cells. Conclusions.— Significant proximal tubular injury occurs associated with LC-ATIN, and the monoclonal light chains accumulated in proximal tubular cells contribute to the injury. Dendritic cells are involved in the pathogenesis of interstitial inflammation in LC-ATIN.

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Intracellular prostaglandin E2 contributes to hypoxia-induced proximal tubular cell death

Scientific Reports ◽

10.1038/s41598-021-86219-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Coral García-Pastor ◽

Selma Benito-Martínez ◽

Ricardo J. Bosch ◽

Ana B. Fernández-Martínez ◽

Francisco J. Lucio-Cazaña

Keyword(s):

Hypoxia Inducible Factor ◽

Renal Diseases ◽

Prostaglandin E ◽

Relevant Factor ◽

Tubular Injury ◽

Proximal Tubular Cells ◽

Tubular Cells ◽

Proximal Tubular ◽

Cox 2 ◽

Induced Apoptosis

AbstractProximal tubular cells (PTC) are particularly vulnerable to hypoxia-induced apoptosis, a relevant factor for kidney disease. We hypothesized here that PTC death under hypoxia is mediated by cyclo-oxygenase (COX-2)-dependent production of prostaglandin E2 (PGE2), which was confirmed in human proximal tubular HK-2 cells because hypoxia (1% O2)-induced apoptosis (i) was prevented by a COX-2 inhibitor and by antagonists of prostaglandin (EP) receptors and (ii) was associated to an increase in intracellular PGE2 (iPGE2) due to hypoxia-inducible factor-1α-dependent transcriptional up-regulation of COX-2. Apoptosis was also prevented by inhibitors of the prostaglandin uptake transporter PGT, which indicated that iPGE2 contributes to hypoxia-induced apoptosis (on the contrary, hypoxia/reoxygenation-induced PTC death was exclusively due to extracellular PGE2). Thus, iPGE2 is a new actor in the pathogenesis of hypoxia-induced tubular injury and PGT might be a new therapeutic target for the prevention of hypoxia-dependent lesions in renal diseases.

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Palmitate aggravates proteinuria-induced cell death and inflammation via CD36-inflammasome axis in the proximal tubular cells of obese mice

AJP Renal Physiology ◽

10.1152/ajprenal.00536.2017 ◽

2018 ◽

Vol 315 (6) ◽

pp. F1720-F1731 ◽

Cited By ~ 8

Author(s):

Lung-Chih Li ◽

Jenq-Lin Yang ◽

Wen-Chin Lee ◽

Jin-Bor Chen ◽

Chien-Te Lee ◽

...

Keyword(s):

Cell Death ◽

Tubular Injury ◽

Proximal Tubular Cells ◽

Tubular Cells ◽

Renal Tubular Cells ◽

Caspase 1 ◽

Proximal Tubular ◽

Renal Tubular ◽

Nlrp3 Inflammasomes

High levels of serum free fatty acids (FFAs) and proteinuria have been implicated in the pathogenesis of obesity-related nephropathy. CD36, a class B scavenger receptor, is highly expressed in the renal proximal tubules and mediates FFA uptake. It is not clear whether FFA- and proteinuria-mediated CD36 activation coordinates NLRP3 inflammasomes to induce renal tubular injury and inflammation. In this study, we investigated the roles of CD36 and NLRP3 inflammasomes in FFA-induced renal injury in high-fat diet (HFD)-induced obesity. HFD-fed C57BL/6 mice and palmitate-treated HK2 renal tubular cells were used as in vivo and in vitro models. Immunohistochemical staining showed that CD36, IL-1β, and IL-18 levels increased progressively in the kidneys of HFD-fed mice. Sulfo- N-succinimidyl oleate (SSO), a CD36 inhibitor, attenuated the HFD-induced upregulation of NLRP3, IL-1β, and IL-18 and suppressed the colocalization of NLRP3 and ASC in renal tubular cells. In vitro, SSO abolished the palmitate-induced activation of IL-1β, IL-18, and caspase-1 in HK2 proximal tubular cells. Furthermore, treatment with SSO and the knockdown of caspase-1 expression by siRNA both inhibited palmitate-induced cell death and apoptosis in HK2 cells. Collectively, palmitate causes renal tubular inflammation, cell death, and apoptosis via the CD36/NLRP3/caspase-1 axis, which may explain, at least in part, the mechanism underlying FFA-related renal tubular injury. The blockade of CD36-induced cellular processes is therefore a promising strategy for treating obesity-related nephropathy.

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Methylation pattern of urinary DNA as a marker of kidney function decline in diabetes

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-001501 ◽

2020 ◽

Vol 8 (1) ◽

pp. e001501

Author(s):

Takeshi Marumo ◽

Junichi Hoshino ◽

Wakako Kawarazaki ◽

Mitsuhiro Nishimoto ◽

Nobuhiro Ayuzawa ◽

...

Keyword(s):

Dna Methylation ◽

Kidney Function ◽

Tubular Injury ◽

Proximal Tubular Cells ◽

Urine Sediment ◽

Tubular Cells ◽

Patients With Diabetes ◽

Proximal Tubular ◽

Renal Tubular ◽

Methylation Patterns

IntroductionRenal tubular injury contributes to the decline in kidney function in patients with diabetes. Cell type-specific DNA methylation patterns have been used to calculate proportions of particular cell types. In this study, we developed a method to detect renal tubular injury in patients with diabetes by detecting exfoliated tubular cells shed into the urine based on tubular cell-specific DNA methylation patterns.Research design and methodsWe identified DNA methylation patterns specific for human renal proximal tubular cells through compartment-specific methylome analysis. We next determined the methylation levels of proximal tubule-specific loci in urine sediment of patients with diabetes and analyzed correlation with clinical variables.ResultsWe identified genomic loci in SMTNL2 and G6PC to be selectively unmethylated in human proximal tubular cells. The methylation levels of SMTNL2 and G6PC in urine sediment, deemed to reflect the proportion of exfoliated proximal tubular cells due to injury, correlated well with each other. Methylation levels of SMTNL2 in urine sediment significantly correlated with the annual decline in estimated glomerular filtration rate. Moreover, addition of urinary SMTNL2 methylation to a model containing known risk factors significantly improved discrimination of patients with diabetes with faster estimated glomerular filtration rate decline.ConclusionsThis study demonstrates that patients with diabetes with continual loss in kidney function may be stratified by a specific DNA methylation signature through epigenetic urinalysis and provides further evidence at the level of exfoliated cells in the urine that injury of proximal tubular cells may contribute to pathogenesis of diabetic kidney disease.

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Immunohistochemical Study of Heat Shock Protein 27 with Respect to Survival and Regeneration of Proximal Tubular Cells after Uranyl Acetate-Induced Acute Tubular Injury in Rats

Renal Failure ◽

10.3109/08860220903367569 ◽

2010 ◽

Vol 32 (1) ◽

pp. 119-125 ◽

Cited By ~ 2

Author(s):

Yoshihide Fujigaki ◽

Yuan Sun ◽

Tomoyuki Fujikura ◽

Yukitoshi Sakao ◽

Akashi Togawa ◽

...

Keyword(s):

Heat Shock ◽

Heat Shock Protein ◽

Immunohistochemical Study ◽

Heat Shock Protein 27 ◽

Uranyl Acetate ◽

Tubular Injury ◽

Proximal Tubular Cells ◽

Tubular Cells ◽

Proximal Tubular

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Diagnostic roles of urinary kidney injury molecule 1 and soluble C5b-9 in acute tubulointerstitial nephritis

AJP Renal Physiology ◽

10.1152/ajprenal.00176.2019 ◽

2019 ◽

Vol 317 (3) ◽

pp. F584-F592 ◽

Cited By ~ 1

Author(s):

Wen-Ting Zhao ◽

Jun-Wen Huang ◽

Ping-Ping Sun ◽

Tao Su ◽

Jia-Wei Tang ◽

...

Keyword(s):

Tubulointerstitial Nephritis ◽

Kidney Injury ◽

Acute Injury ◽

Tubular Injury ◽

Acute Tubulointerstitial Nephritis ◽

Tubular Cells ◽

Renal Tubular Cells ◽

Interstitial Inflammation ◽

Renal Tubular ◽

Kidney Injury Molecule 1

Acute tubulointerstitial nephritis (ATIN) is a common cause of acute kidney injury characterized by inflammatory cells infiltrating in the interstitium. The present study aimed to explore noninvasive biomarkers that might indicate activity of pathological injuries and help direct treatment. Fifty-four patients with clinical-pathologically diagnosed ATIN from January 1, 2014, to June 30, 2016, at Peking University First Hospital were enrolled. Urine samples were collected on the morning of renal biopsy and assessed for urinary kidney injury molecule-1 (KIM-1) and urinary soluble C5b-9 (sC5b-9). Immunofluorescence staining for KIM-1 and C5b-9 was performed in biopsied kidney sections from ATIN cases. The clinical and pathological relevance of the two urinary biomarkers was analyzed. Both urinary KIM-1 and sC5b-9 values were significantly elevated in patients with ATIN compared with healthy controls. The urinary KIM-1 level positively correlated with urinary N-acetyl-β-d-glucosaminidase ( r = 0. 542, P = 0.001) and the pathological tubular injury score ( r = 0.469, P < 0.001), whereas the urinary sC5b-9 level was related to pathological activity scores for tubular injury ( r = 0.413, P = 0.002), interstitial inflammation ( r = 0.388, P = 0.004), and treatment response ( r = 0.564, P < 0.001). Urinary KIM-1 tended to have better diagnostic value for tubular injury than urinary sC5b-9, whereas only urinary sC5b-9 was able to demonstrate severe interstitial inflammation. A combination of urinary KIM-1 and sC5b-9 had an area under the receiver-operating characteristic curve of 0.864 (95% confidence interval: 0.766–0.963, P < 0.001, sensitivity: 75%, specificity: 88%) for acute tissue injury in ATIN. KIM-1 expression was markedly increased in renal tubular cells in both ATIN and acute tubular necrosis conditions, whereas a significant upregulation of C5b-9 was only detected in the tubular cells and interstitial cells in ATIN cases. Urinary KIM-1 is a specific biomarker for renal tubular injury in ATIN, whereas urinary sC5b-9 is valuable in demonstrating severe interstitial inflammation. The combination of these two biomarkers helps identify patients at an acute injury stage and, therefore, might facilitate clinical evaluation and guide immunosuppressive therapy.

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