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. 2024 Oct 3;98(12):3973–3986. doi: 10.1007/s00204-024-03868-2

Thallium reabsorption via NKCC2 causes severe acute kidney injury with outer medulla-specific calcium crystal casts in rats

Kana Unuma 1,✉, Shuheng Wen 1, Sho Sugahara 1, Shutaro Nagano 1, Toshihiko Aki 1, Tadayuki Ogawa 2, Shino Takeda-Homma 3, Masakazu Oikawa 3, Akihiro Tojo 4
PMCID: PMC11496332  PMID: 39361050

Abstract

Thallium (Tl) is one of the most toxic heavy metals, associated with accidental poisoning and homicide. It causes acute and chronic systemic diseases, including gastrointestinal and cardiovascular diseases and kidney failure. However, few studies have investigated the mechanism by which Tl induces acute kidney injury (AKI). This study investigated the toxic effects of Tl on the histology and function of rat kidneys using biochemical and histopathological assays after intraperitoneal thallium sulfate administration (30 mg/kg). Five days post-administration, rats exhibited severely compromised kidney function. Low-vacuum scanning electron microscopy revealed excessive calcium (Ca) deposition in the outer medulla of Tl-loaded rats, particularly in the medullary thick ascending limb (mTAL) of the loop of Henle. Tl accumulated in the mTAL, accompanied by mitochondrial dysfunction in this segment. Tl-loaded rats showed reduced expression of kidney transporters and channels responsible for Ca2+ reabsorption in the mTAL. Pre-administration of the Na–K–Cl cotransporter 2 (NKCC2) inhibitor furosemide alleviated Tl accumulation and mitochondrial abnormalities in the mTAL. These findings suggest that Tl nephrotoxicity is associated with preferential Tl reabsorption in the mTAL via NKCC2, leading to mTAL mitochondrial dysfunction and disrupted Ca2+ reabsorption, culminating in mTAL-predominant Ca crystal deposition and AKI. These findings on the mechanism of Tl nephrotoxicity may contribute to the development of novel therapeutic approaches to counter Tl poisoning. Moreover, the observation of characteristic Ca crystal deposition in the outer medulla provides new insights into diagnostic challenges in Tl intoxication.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00204-024-03868-2.

Keywords: Thallium, Kidney toxicity, Medullary thick ascending limb, Calcium deposits, Rat model

Introduction

Thallium (Tl) is a toxic metal element widely dispersed in the natural environment (Genchi et al. 2021; Sánchez-Chapul et al. 2023). Historically, it was used to treat gonorrhea, syphilis, and tuberculosis and as a rodenticide (Smith and Carson 1977). However, currently, its use is severely restricted owing to safety concerns and is confined to myocardial scintigraphy (Strauss and Bailey 2009). Tl is more toxic than other heavy metals such as arsenic, cadmium, and mercury (Fisher and Gupta 2024). Overdose owing to attempted homicide, suicide, or occupational exposure has severe life-threatening clinical manifestations (Osorio-Rico et al. 2017; Duan et al. 2020). Tl is distributed throughout the organism after ingestion. As Tl is similar to potassium (K) cations in terms of charge and atomic radius, Tl has been hypothesized to enter cells actively via Na+/K+-ATPase or passively via K+ channels (Britten and Blank 1968; Peter and Viraraghavan 2005). Tl exhibits cardiac, neurological, gastrointestinal, and renal toxicity (Roby et al. 1984; Cvjetko et al. 2010) and can cause death within 1 week of exposure (Al Hammouri et al. 2011; Riyaz et al. 2013). At least 119 cases of acute Tl poisoning have been reported worldwide since 2011 (Yan et al. 2011; Liao et al. 2012; López Segura et al. 2013; Riyaz et al. 2013; Huang et al. 2014; Li et al. 2015; Sojáková et al. 2015; Campbell et al. 2016; Kuroda et al. 2016; Senthilkumaran et al. 2017; Yumoto et al. 2017; Matsukawa et al. 2018; Yang et al. 2018; Lin et al. 2019; Liu and Liao 2021; Rossetto et al. 2021; Pragst and Hartwig 2022; Jimenez et al. 2023). Diagnosis of Tl intoxication is challenging in the initial stages because of the lack of characteristic clinical manifestations other than alopecia (Yang et al. 2018; Liu and Liao 2021). Tl elimination is predominantly via the kidneys but is incomplete and slow, resulting in Tl accumulation in the kidney (Ríos et al. 1989; Leung and Ooi 2000; Sánchez-Chapul et al. 2023). However, limited information is available on the mechanisms underlying Tl-induced nephrotoxicity. Thus, this study aimed to investigate the mechanism underlying acute Tl-induced nephrotoxicity in experimental rats.

Materials and methods

Animals and Tl administration

All animal experiments were approved by the Institutional Animal Care and Use Committee of Tokyo Medical and Dental University (approval No. A2023-080C) and were performed in accordance with the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines. Eight-week-old male Wistar rats weighing 220–250 g (Oriental Yeast Co. Ltd., Tokyo, Japan) were maintained in standardized conditions (12-h light/dark cycles, 25 °C) with ad libitum access to water and food. The rats were randomly divided into control and Tl groups. Each rat received a single intraperitoneal injection of either double-distilled water or 30 mg/kg thallium sulfate (Tl2SO4) (Fujifilm Wako Pure Chemical Corporation, Osaka, Japan) dissolved in double-distilled water, and samples were collected 2 or 5 days later. For the 2-day protocol, each group included four male rats. For the 5-day protocol, 15 and 8 male rats were included in the Tl and control groups, respectively. Three or four rats per group were used for each analysis. The 30 mg/kg Tl dose was selected based on the dose used in a previous study of acute Tl toxicity (Danilewicz et al. 1979; Leung and Ooi 2000). Tl distribution and production of reactive oxygen species (ROS) in the kidneys were also analyzed in another group of rats 4 h after injection of 120 mg/kg Tl2SO4 with or without pre-administration of 20 mg/kg of intraperitoneal furosemide as a Na–K–Cl cotransporter 2 (NKCC2) inhibitor (Dagan et al. 2009). The rats were euthanized at the specified time-point by intraperitoneal sodium pentobarbital (100 mg/kg) administration and their kidneys were excised (Fig. 1). Body and kidney weights were recorded for each rat.

Fig. 1.

Fig. 1

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Severely abnormal kidney function 5 days after Tl administration. Timeline of the experimental procedure (a). Eight-week-old Wistar rats received a single administration of 30 mg/kg or the same volume of double-distilled water and were sacrificed 2 or 5 days later, with kidneys collected for subsequent analysis. Kidney weight 5 days after Tl administration (b). Analysis of blood (c) and urine (d) samples collected 5 days after Tl administration of rats. Each bar represents the mean and standard deviation. Ns not significant; *P < 0.05; **P < 0.01; ***P < 0.001. ALB albumin; BUN blood urea nitrogen; Ca calcium; Cl chloride; Cre creatinine; IP inorganic phosphorus; K potassium; Mg magnesium; Na sodium; NAG N-acetyl-β-D-glucosaminidase; TP total protein; U- urinary level of; UA uric acid; UN urea nitrogen

Blood/urine analysis and kidney ultrasonography

Blood samples (anticoagulant in the syringe: 1.5 mg/mL K3-EDTA) and urine samples (12-h metabolic cage at 25 °C) were collected from the rats 5 days after administering Tl (30 mg/kg). The plasma and/or urine levels of albumin (Alb), blood urea nitrogen (BUN), creatinine (Cre), inorganic phosphorus (IP), uric acid (UA), sodium (Na), K, chlorine (Cl), calcium (Ca), total protein (TP), magnesium (Mg), and N-acetyl-β-D-glucosaminidase (NAG) were then measured according to the standard methods of Oriental Yeast Co. Ltd. (Tokyo, Japan). Urine proteins were fractionated using sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE), with the loading sample corrected for specific gravity.

Ultrasound (Noblus, Hitachi-Aloka Medical Ltd., Tokyo, Japan) was used to observe kidney stones on days 2 and 5 after administering Tl.

Detection of mitochondrial production of ROS

Rats in the 4-h group were euthanized 4 h after administering Tl2SO4. Their kidneys were removed and sliced into 10-μm-thick cryosections. Mitochondrial ROS production was assessed using a fluorometric mitochondria superoxide assay. Cryosections were incubated with MitoROS 520 (AATBioquest Inc, Cosmo Bio Co., Tokyo, Japan) in assay buffer for 1 h at 37 °C and observed under a fluorescence microscope (Keyence BZ-9000, Keyence, Osaka, Japan) with an excitation wavelength of 540 nm and emission wavelength of 590 nm.

Histological analysis and immunohistochemistry

Central short-axis cross-sections of the rat kidney were fixed in 4% paraformaldehyde, embedded in paraffin, and sliced into 2.5-µm-thick sections. For histological analysis, the sections were stained with hematoxylin and eosin (H&E), von Kossa, and Alizarin red for Ca crystals and with De Galantha for UA crystals. Immunohistochemical (IHC) analysis was performed as previously described (Taal et al. 2012; Unuma et al. 2013a, b). Paraffin-embedded sections were deparaffinized, and antigenicity was retrieved by microwave heating. The sections were incubated with a 1:100 dilution of rabbit polyclonal anti-Ca2+-ATPase antibody (Cosmo Bio Co. Ltd., Tokyo, Japan), followed by a 1:400 dilution of horseradish peroxidase (HRP)-labeled anti-rabbit Ig antibody (Dako, Glostrup, Denmark). HRP labeling was detected using a peroxidase substrate solution with 0.8 mM diaminobenzidine and 0.01% H2O2 (Tojo et al. 2008).

Electron microscopy

Electron microscopy of the rat kidney was performed as previously described (Tojo et al. 2008; Unuma et al. 2013a, b). Briefly, central short-axis cross-sections of the kidney were fixed with 2.5% glutaraldehyde, followed by 1% osmium tetroxide, and embedded in epoxy resin. Ultra-thin sections were stained with uranyl acetate and lead citrate and observed under a transmission electron microscope (HT7800, Hitachi High-Tech Co., Tokyo, Japan). Epoxy resin blocks or 200-μm vibratome slices from 2.5% glutaraldehyde-fixed kidneys were directly observed using low-vacuum scanning electron microscopy (LVSEM, TM4000Plus, Hitachi High-Tech Co., Tokyo, Japan) with an acceleration voltage of 10 kV (Tojo et al. 2023).

Elemental analysis of the kidney, urinary crystals, and Tl distribution and imaging

After Tl administration, elemental analysis of the kidney and urinary crystals on 200-μm vibratome kidney slices and urinary sediment was performed using LVSEM (TM4000Plus or TM3030) equipped with an energy dispersive X-ray spectroscopy system (AZtecOne software, Oxford Instruments Nanoanalysis, High Wycombe, UK) at an accelerating voltage of 15 kV in the highest beam current mode (Lens mode 4) in a vacuum (< 50 Pa). Tl distribution in the kidneys of Wistar rats was assessed 10-μm-thick cryosections of the kidneys harvested 4 h after 120 mg/kg Tl2SO4 administration using particle-induced X-ray emission (PIXE).

Ca, Cl, K, phosphorus (P), sulfur (S), and silicon (Si) distributions were determined by micro-PIXE (μPIXE) analysis using a Model OM-2000 microbeam scanning PIXE system (Oxford Microbeams Ltd., Oxford, UK) with an Si (Li) X-ray detector (Gresham Sirius80, active area: 80 mm2; Gresham Power Electronics, Salisbury, UK) (Ishikawa et al. 2009). Tl, zinc (Zn), and iron (Fe) distributions were determined by μPIXE analysis using a CdTe X-ray detector (XR-100 T-CdTe, active area: 25 mm2; Amptek, Bedford, MA, USA), with high X-ray absorbency for detecting elements with high Z atomic numbers and high density (5.85 g/mL) for efficient detection of X-rays (10–20 keV) emitted by heavy elements (Homma-Takeda et al. 2010). Elemental images were constructed using the intensity data of the Kα (laser ablation for Tl) lines at each point by scanning the specimens under the following conditions: proton energy, 3.0 MeV; integrated current, 0.2 μC; and beam size, 1 × 1 μm. Dissolution studies were conducted on unstained paraffin-embedded rat kidney sections to identify the composition of Ca-containing crystals in the outer medulla using 10% acetic acid, 10% hydrochloric acid, and 10% sodium hydroxide.

DNA microarray and qPCR analysis

RNA was isolated using TRIzol reagent (Thermo Fisher Scientific, Waltham, MA, USA) and purified using an RNeasy RNA Purification Kit (Qiagen, Hilden, Germany) for DNA microarray analysis. The RNA integrity was assessed using a BioAnalyzer (Agilent Technologies, Santa Clara, CA, USA) and hybridized using a Clariom S array (Thermo Fisher Scientific). The DNA microarray results were analyzed using Transcriptome Analysis Console software (Thermo Fisher Scientific). cDNA was synthesized for quantitative reverse transcription-mediated real-time polymerase chain reaction (qPCR) analysis using SuperScript II Reverse Transcriptase (Thermo Fisher Scientific). A StepOnePlus Real-Time PCR System (Thermo Fisher Scientific) was used for qPCR. The relative abundance of RNA was computed, and the amplification products were detected using the comparative cycle threshold (Ct) method and SYBR Green fluorescence dye. Supplementary Table 1 lists the primers used.

Statistical analysis

Dunnett’s post-hoc test was used for comparisons between groups. Two-tailed P values < 0.05 were considered statistically significant. Statistical analyses were performing using GraphPad Prism (Version 9.0.0, GraphPad Software, San Diego, CA, USA).

Results

Kidney function in rats 5 days after Tl administration

Five days after Tl administration, rats in the Tl group had a markedly higher kidney weight than those in the control group (Fig. 1b). Blood BUN, Cre, and IP levels were significantly increased and Cl and Ca levels were significantly decreased in the Tl group compared with those in the control group (Fig. 1c). Urine Alb levels were significantly increased and CRE, BUN, UA, Na, K, Cl, and Mg levels were decreased in the Tl group compared with those in the control group (Fig. 1d). However, the NAG level, a marker of proximal tubular damage, did not differ between groups (Fig. 1d). Urine SDS-PAGE analysis suggested a combination of glomerular and tubular dysfunction in Tl-loaded rats with increased excretion of both larger proteins and low-molecular-weight proteins (Supplementary Fig. 1). These findings indicate that rats had severely compromised kidney function 5 days after Tl administration, manifesting as abnormal excretion and reabsorption.

Kidney Ca deposits 5 days after Tl administration

H&E staining revealed no abnormalities in the kidneys of control rats (Fig. 2a); however, H&E staining of short-axis kidney cross-sections of Tl-loaded rats revealed basophilic deposits in the kidney tubules of the outer medulla of all Tl-loaded rats (Fig. 2b, c), manifesting as blue polarization under dark-field microscopy (Fig. 2d). von Kossa and Alizarin red S staining confirmed deposits of Ca-containing salts in kidney sections of Tl-loaded rats (Fig. 2e, f) (Shavit et al. 2015). Five days after Tl administration, the Ca deposits were localized to the outer medulla of the kidney (Fig. 2e, f). To identify the segmental distribution of Ca deposits in the outer medulla, 200-μm-thick fresh vibratome kidney sections were viewed using LVSEM. No deposits were observed on the kidney slices of control rats (Fig. 3a), whereas the tubules in the outer medulla of the Tl-loaded rats were blocked by extensive columnar-shaped deposits (Fig. 3b–d). LVSEM revealed numerous granular crystals forming columnar casts within the tubules of the loop of Henle and epithelial flattening without a brush border membrane (Fig. 3c, d). The morphology of epoxy resin blocks of the kidney outer medulla on electron microscopy confirmed that the Ca deposits were primarily localized in the mTAL (Fig. 3e–h) (Galantha 1935). High-magnification images revealed fully formed deposits completely obstructing the mTAL lumen (Fig. 3f, g) and granular crystal fragment aggregations covering desquamated mTAL epithelial cells (Fig. 3h), suggesting the presence of Ca crystals. These findings indicate that Tl-induced Ca crystal deposition predominantly in the mTAL, causing structural kidney damage.

Fig. 2.

Fig. 2

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Calcium deposits in the kidney 5 days after Tl administration. Hematoxylin and eosin (H&E) staining (a–d), von Kossa staining (e), and Alizarin S staining (f) of kidney sections from control rats (a), Tl rats (b–f) 5 days after Tl administration (30 mg/kg). Dark-field observation of H&E staining of the kidney sections from Tl group rats (d). Scale bars indicate 100 μm

Fig. 3.

Fig. 3

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Low-vacuum scanning electron microscopy images of Tl-induced calcium deposits in the outer medulla. Low-vacuum scanning electron microscopy (LVSEM) observation of 200-μm vibratome sections (a–d) and epoxy resin blocks (e–h) of the kidneys from control (a) and Tl group (30 mg/kg) rats (b–h). *Outer medullary collecting ducts in the medullary rays. Crystal deposits completely obstruct the mTAL lumen (white arrows), and granular crystal aggregations cover the desquamated mTAL epithelial cells (hollow white arrows). mTAL medullary thick ascending limb of the loop of Henle; OMCD outer medullary collecting duct; S3 proximal straight tubule; TL thin limb of the loop of Henle. The observation conditions and magnifications are presented at the bottom of the figures at a magnification of × 80 (a, b), × 200 (c), × 4000 (d), × 100 (e), × 400 (f), and × 800 (g, h) (colour figure online)

Dissolution experiments and elemental analysis revealed that the Ca deposits were primarily calcium bicarbonate (CaCO3) with smaller amounts of calcium phosphate (Ca3(PO4)2), ammonium magnesium phosphate (NH4MgPO4 6H2O), calcium oxalate (Ca(C2O4) 2H2O), and UA (C5H4N4O3) (Supplementary Figs. 2, 3a–g). Elemental analysis of the urinary crystals excreted by Tl-loaded rats revealed consistent findings (Supplementary Fig. 3 h–n).

Effect of furosemide pre-administration on Tl accumulation in the mTAL

Because minimal Tl was detectable in the kidney at 5 days, we performed an elemental analysis of rat kidneys 4 h after Tl2SO4 administration to assess Tl distribution within the kidney (Supplementary Fig. 3g). Tl was distributed mostly as small particles in the outer medullary layer and weakly distributed in the inner medullary layer and the cortex (Fig. 4a). Four hours after Tl2SO4 administration, Ca, P, and K had already accumulated predominantly in the outer medulla (Fig. 4b). Tl particles were also present in kidney tubular cells of the outer medulla (Fig. 4c, Supplementary Fig. 4). In addition, we performed an elemental analysis of the kidney after administering furosemide, a Na–K–Cl cotransporter (NKCC) inhibitor, before Tl administration. The Tl concentration in the outer medulla was significantly lower in the furosemide pretreatment group than in the group that did not undergo furosemide pretreatment, measuring 0.01 ± 0.01% and 0.25 ± 0.10%, respectively (Fig. 4d, e). These findings suggest that Tl is preferentially reabsorbed in the mTAL via NKCC2, which may be associated with the predominant Ca deposits in mTAL following Tl administration.

Fig. 4.

Fig. 4

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Tl accumulation in the medullary thick ascending limb (mTAL) of the outer medulla (OM) after Tl administration with or without furosemide pretreatment. Elemental distribution in the cortex (Cx), OM, and inner medulla (IM) of frozen kidney sections of Tl-loaded rats after 4 h (120 mg/kg). Elemental imaging (scanned area, 500 μm × 500 μm; integrated current) of the Cx, OM, and IM of the kidney. Serial cryosections were stained with hematoxylin and eosin (H&E) (a). Particle-induced X-ray emission (PIXE) spectra of Tl were obtained by scanning positions Cx, OM, and IM (b, c). Tl thallium; Zn zinc; Fe iron; Ca calcium; Cl chloride; K potassium; P phosphorus; S sulfur; Si silicon. Elemental distribution in Cx, OM, and IM with or without furosemide 4 h after Tl administration (d). Comprehensive result of elemental analysis of the Cx, OM, and IM of frozen kidney sections of rats after Tl administration with or without furosemide (e). Scale bars = 500 μm (b), 100 μm (c). Cx cortex, OM outer medulla, IM inner medulla, Tl thallium group rats, Fr + Tl furosemide-treated rats before thallium injection. *P < 0.05 when compared to the Tl group (e)

Effect of furosemide pre-administration on mitochondrial abnormalities in the mTAL after Tl administration

Given the prominent mTAL damage and Ca deposition in Tl-loaded rats at 30 mg/kg, we investigated whether Tl aggregation specifically in the mTAL led to more severe mitochondrial dysfunction in this kidney segment than in other segments. The fluorometric mitochondria superoxide assay revealed that 4 h after Tl administration at 120 mg/kg, mitochondrial ROS were mainly localized in the outer medulla (Fig. 5A). High-magnification images revealed that mitochondrial ROS were located among the mTAL, consistent with the localization observed upon Alizarin red staining (Figs. 2f, 5A). Pretreatment with furosemide reduced mitochondrial ROS levels in the outer medulla (Fig. 5A). These findings suggest that Tl accumulation in the mTAL stimulated the mitochondria and generated ROS, which was prevented by inhibiting NKCC2. Moreover, transmission electron microscopy conducted on the kidneys of Tl-loaded rats 2 days after 30 mg/kg Tl administration revealed mild podocyte foot process abnormalities with no significant pathological changes observed in segments other than the mTAL (Fig. 5B, Supplementary Fig. 5). The mTAL exhibited vacuolar degeneration accompanied by mitochondrial swelling and mitochondrial cristae fragmentation and disarrangement (Fig. 5B). Pre-administration furosemide alleviated the vacuolar degeneration and desquamation of the mTAL 4 h after 120 mg/kg Tl administration (Fig. 5C). These findings suggest that mTAL-specific aggregation of Tl led to marked mitochondrial ROS production and localized damage in this segment.

Fig. 5.

Fig. 5

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Mitochondrial disorders in mTAL and mTAL damage after Tl administration with or without furosemide pretreatment. Mitochondrial production of ROS in the OM of the kidneys of male Wistar rats 4 h after Tl administration (120 mg/kg), with (A-b, d) and without furosemide pretreatment (A-a, c), showing inhibition of Tl-induced mitochondrial ROS in the OM by furosemide. Scale bar = 50 μm (A, a-d). Transmission electron microscopy of kidney sections from Tl-loaded rats 2 days after Tl administration (B). Medullary thick ascending limb of the loop of Henle (B-a), mitochondria in the medullary thick ascending limb of the loop of Henle (B-b). LVSEM analysis of the kidney 4 h after Tl administration with (C-b, d) or without (C-a, c) pre-administration of furosemide (20 mg/kg). Tubular necrosis and desquamation of the OM due to Tl administration were reduced by furosemide; vacuolar degeneration and desquamation of mTAL were present (arrows) but were reduced by furosemide pretreatment. The observation conditions and magnifications are shown at the bottom of figures (B, C). LVSEM low-vacuum scanning electron microscopy; mTAL medullary thick ascending limb of the loop of Henle; OM outer medulla; ROS reactive oxygen species

Expression of kidney transporter and channel genes and Ca2+-ATPase 5 days after Tl administration

DNA microarray analysis revealed a significant downregulation of most kidney transporter channel genes in the Tl-loaded rats compared with that in control rats 5 days after Tl administration (Tables 1 and 2). Ca reabsorption in the mTAL relies primarily on the electrochemical gradients established by transport and channels such as NKCC2, renal outer medullary potassium channel (ROMK, potassium inwardly rectifying channel 1.1 [Kir1.1]), potassium inwardly rectifying channel 4.1 (Kir4.1), and Na+/K+-ATPase (Mount 2014). qPCR analysis confirmed that the expression of the genes for these transporters and channels was significantly downregulated in the kidneys of Tl-loaded rats compared with those of control rats (Fig. 6a).

Table 1.

Top 10 upregulated or downregulated genes in the kidney of Tl-loaded rats in order of fold change

Gene symbol Fold change Description
Top 10 upregulated genes in the kidney in order of fold change (Tl group compared with the control group)
 Havcr1  + 7890.49 Hepatitis A virus cellular receptor 1
 Ngal  + 350.01 Neutrophil gelatinase-associated lipocalin
 Hmgcs2  + 262.72 3-hydroxy-3-methylglutaryl-CoA synthase 2 (mitochondrial)
 Vnn1  + 228.67 Vanin1
 Clu  + 177.87 Clusterin
 Tmem252  + 101.81 Transmembrane protein 252
 Cyp24a1  + 92.43 Cytochrome P450, family 24, subfamily a, polypeptide 1
 Mt1f  + 82.47 Metallothionein 1F
 Gdf15  + 60.6 Growth differentiation factor 15
 Spp1  + 58.16 Secreted phosphoprotein 1, osteopontin
Top 10 downregulated genes in kidney in order of fold change (Tl group compared with the control group)
 Slc7a12  − 953.49 Cationic amino acid transporter, y + system
 Cacng5  − 805.25 Voltage-dependent calcium channel gamma 5 subunit
 Umod  − 702 Uromodulin
 Rgn  − 241.77 Regucalcin
 Slco1a6  − 146.48 Solute carrier organic anion transporter family, member 1a6
 Slco1a1  − 142.83 Solute carrier organic anion transporter family, member 1a1
 Calb1  − 88.61 Calbindin1
 Slc7a13  − 43.79 Cationic amino acid transporter, y + system
 Slc16a7  − 30.5 Monocarboxylate transporter 2
 Slc26a7  − 26.37 Anion exchange transporter
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Table 2.

Expression of major kidney transporter and channel genes in the kidney of Tl-loaded rats in order of fold change (Tl group compared with the control group)

Gene symbol Fold change Description
Calb1  − 88.61 Calbindin 1
Slc8a1  − 23.66 Sodium/calcium exchanger 1
Casr  − 12.36 Calcium-sensing receptor
Kcnj10  − 11.56 ATP-sensitive inward rectifier potassium channel 10
Kcnj1  − 11.55 ATP-sensitive inward rectifier potassium channel 1
Slc12a1  − 8.17 Sodium–potassium-chloride cotransporter 2
Slc12a3  − 6.98 Na-Cl cotransporter
Slc9a3  − 6.98 Sodium/hydrogen exchanger 3
Slc4a1  − 5.78 Anion exchange protein 1
Aqp2  − 5.75 Aquaporin 2
Aqp6  − 3.92 Aquaporin 6
Aqp7  − 1.91 Aquaporin 7
Kcnq1  − 1.72 Potassium voltage-gated channel subfamily Q member 1
Aqp3  − 1.59 Aquaporin 3
Kcnma1  − 1.54 Potassium calcium-activated channel subfamily M alpha 1
Scnn1a  − 1.21 Sodium channel epithelial 1 subunit alpha
Slc5a1  − 1.05 Sodium/glucose cotransporter 1
Slc20a2  − 1 Sodium-dependent phosphate transporter 2
Aqp1  + 1.08 Aquaporin 1
Atp1a1  + 1.12 Sodium–potassium-ATPase, alpha 1 subunit
Slc5a2  + 1.23 Sodium/glucose cotransporter 2
Atp2c2  + 1.36 Ca-ATPase
Slc22a12  + 1.68 Urat1
Trpv5  + 3.12 Calcium transport protein 2
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Fig. 6.

Fig. 6

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Downregulated expression of kidney transporter and channel genes and Ca2+-ATPase 5 days after Tl administration at 30 mg/kg. Quantitative real-time PCR analysis of genes encoding mTAL-related kidney transporters and channels (a). GAPDH, glyceraldehyde-3-phosphate dehydrogenase; Kir 1.1, potassium inwardly rectifying channel subfamily J member 1; Kir 4.1, potassium inwardly rectifying channel subfamily J member 10; NaK-ATP, Na+/K+ transporting ATPase alpha 1 subunit; NKCC2, Na–K–Cl cotransporter 2. GAPDH levels served as an internal control. *P < 0.05; **P < 0.01; ***P < 0.001. Immunohistochemistry of Ca2+-ATPase in the outer and inner medullae of rats in the control and Tl-loaded groups (b). Ca2+-ATPase expression is decreased in the mTAL obstructed by calcium deposits (*)

IHC analysis to examine the expression of Ca2+-ATPase, which regulates intracellular homeostasis and contributes to the paracellular reabsorption of Ca in the mTAL, revealed similar levels of expression in the inner medulla of Tl-loaded and control rats. However, the obstruction of the mTAL by Ca deposits in Tl-loaded rats (Fig. 6b) suggests that Ca reabsorption was severely compromised 5 days after Tl administration, possibly involving the formation of Tl-induced Ca deposits in the mTAL.

Discussion

This study revealed severely abnormal kidney function in rats 5 days after 30 mg/kg Tl administration, characterized by compromised excretion and reabsorption and proteinuria (Herman and Bensch 1967; Appenroth et al. 1995). A novel finding is that Tl administration led to Tl preferential accumulation in the mTAL of the outer medulla, leading to mTAL-specific tubular damage and Ca deposits, with only mild changes in the proximal tubules. This finding challenges the prevailing view that because of the similarity between Tl+ and K+, the tissue distribution of Tl is closely linked to Na+/K+-ATPase, which primarily functions in the proximal tubules (Britten and Blank 1968; Jørgensen 1980; Sehweil et al. 1989; Peter and Viraraghavan 2005). Some studies have attributed the higher concentration of Tl in the kidney medulla to the significantly increased Na+/K+-ATPase activity in this region (Appenroth et al. 1995, 1996; Appenroth and Winnefeld 1999). However, this does not explain why the Tl concentration in the kidney medulla was 4.10-fold higher than that in the kidney cortex, whereas the Na+/K+-ATPase activity in the medulla was only 2.16-fold higher than that in the cortex. Inhibition of the NKCC2 channel, which is selectively expressed in the apical membrane of the mTAL (Castrop and Schnermann 2008), mitigated preferential Tl accumulation in the medulla and mitochondrial abnormalities in the mTAL, suggesting that the kidney reabsorption of Tl involves mTAL-specific NKCC2 channels.

The mTAL segment plays a crucial role in Ca2+ reabsorption (Greger 1985; Mount 2014). PCR and IHC analysis revealed that the function of all transporters and channels associated with Ca2+ reabsorption was abnormal in the mTAL after Tl administration. Previous studies have reported maximum mTAL destruction on day 2 after Tl administration (Danilewicz et al. 1980; Appenroth et al. 1995). The kidney ultrasonography findings revealed kidney deposits appearing as early as the second day after Tl administration (Supplementary Fig. 6). Additionally, microarray analysis revealed significantly decreased expression of Umod (Table 1), predominantly produced by the mTAL, which encodes a protein critical for kidney ion transportation and protection against kidney stones, 5 days after Tl administration. Thus, Tl-induced mTAL-specific kidney Ca deposits are associated with Tl preferential accumulation in the mTAL, driven by mTAL-specific NKCC2, leading to disrupted Ca2+ reabsorption and a dysregulated uromodulin for preventing kidney stones. Ultrasonographic studies are needed to investigate whether Tl intoxication in humans results in similar mTAL-specific Ca deposits, as ultrasonography (Supplementary Fig. 6), computed tomography, LVSEM in renal biopsy, and elemental analysis using kidney and urinary sediments (Supplementary Fig. 3) could facilitate the diagnosis of Tl intoxication.

Tl exhibits cellular toxicity by causing abnormal mitochondrial function and reduced defense against ROS via mechanisms such as reduction in the glutathione concentration (Bragadin et al. 2003; Hanzel and Verstraeten 2006; Cvjetko et al. 2010; Anaya-Ramos et al. 2021). However, evidence regarding the involvement of glutathione in Tl-induced acute kidney injury (AKI) is conflicting (Appenroth et al. 1996). Furthermore, Tl deposits can cause oxidation of membrane lipids, leading to disruption of membrane-associated metabolic processes, and can trigger reticulum stress related to the promotion of paraptosis (Cvjetko et al. 2010; Morel Gómez et al. 2023). This study revealed that Tl administration induced mitochondrial dysfunction in the mTAL, resulting in vacuolar degeneration and desquamation of the mTAL epithelial cells, compromised function of transporters and channels related to Ca reabsorption, and Ca deposits within the mTAL. However, the precise mechanism underlying Tl toxicity in mTAL epithelial cells remains unclear.

In conclusion, this study demonstrated that Tl induces Ca deposits in the kidney medulla, primarily associated with the mTAL. The deposits are linked to preferential Tl accumulation in the mTAL via the NKCC2 channel and a cytotoxic effect on mTAL epithelial cells, resulting in nephron obstruction and severely abnormal kidney function. These findings improve our understanding of Tl nephrotoxicity and could facilitate the development of novel diagnostic and therapeutic strategies against Tl intoxication.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 1621 KB) (1.6MB, pdf)

Acknowledgements

We thank Mr. Hiroaki Ito, Ms. Mami Konomi, Ms. Kaoru Ichikawa, and Mr. Makoto Nakabayashi at Hitachi Hightech for their support and imaging of elemental analysis of the kidney and urinary stones and Iso H., Higuchi Y., and Matsuda T. at the National Institutes for Quantum Science and Technology for technical assistance with PIXE imaging. We also thank Mr. Kinichi Matsuyama of the Department of Pathology, Dokkyo Medical University, for helping with transmission electron microscopy and Ms. Noriko Oshima of the Center for Research Support, Dokkyo Medical University, for histochemistry and immunostaining. The PIXE experiment was performed under the Joint-use Research Facility for Collaborative Project with IQMS-PASTA, Project No. 21PJ13 (TO).

Funding

This research was funded by the Ministry of Education, Culture, Sports, Science, and Technology (22K10606 to KU, and 20H03955 to TA) and was partially supported by a research donation to AT by Dr. Naohiko Kobayashi, Director of Kobayashi Medical Clinic, Yasuzuka, Japan (#2022-7, #2023-9).

Data availability

The authors confirm that the data supporting the findings of this study are available in the article and its supplementary materials. Gene expression data have been deposited in GEO datasets under accession code GSE269635.

Declarations

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

The study did not involve clinical studies or patient data. All animal experiments were approved by the Institutional Animal Care and Use Committee of Tokyo Medical and Dental University (Permit No. A2023-080A) and were performed according to the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines.

Footnotes

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary file1 (PDF 1621 KB) (1.6MB, pdf)

Data Availability Statement

The authors confirm that the data supporting the findings of this study are available in the article and its supplementary materials. Gene expression data have been deposited in GEO datasets under accession code GSE269635.

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