Research ArticleExperimental Studies
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Decreased SMP30 Expression Is Related With EMT in the Kidneys of Two Siberian Tigers With CKD

YI-RANG JUNG, JAE-HYUK YIM, YOUNG-JIN LEE, SAE-BOM LEE, SUNG-YONG HEO, SEUL-GI BAE, KYOO-TAE KIM, YOUNG-SAM KWON, SANG-JOON PARK, JIN-KYU PARK and TAE-HWAN KIM
In Vivo January 2024, 38 (1) 226-234; DOI: https://doi.org/10.21873/invivo.13429

Abstract

Background/Aim: Chronic kidney disease (CKD) is one of the most common causes of mortality in wild non-domestic felidae. The molecular mechanism regulating renal fibrosis in nephropathy is not fully understood especially in the felidae. This study aimed to elucidate senescence marker protein 30 (SMP30) expression patterns and its relationship with epithelial–mesenchymal transition (EMT) by immunostaining in two necropsied Siberian tigers (Panthera tigris altaica) with CKD. Materials and Methods: Two kidney samples from male Siberian tigers were fixed and tissue sections were stained for histopathological assay. Results: In CKD, renal tubular epithelial cells lost their tubular structures surrounded by severe interstitial fibrosis and were detached from the basement membrane. These damaged cells resembled the morphology of mesenchymal cells and showed much lower SMP30 expression compared with intact tubular epithelial cells. These cells also expressed vimentin, which is specifically expressed by mesenchymal cells, and through double staining, it was observed that vimentin was expressed in the tubular epithelial cells where SMP30 was not expressed. In addition, double-positive expression of pan-cytokeratin (pan-CK) and vimentin was found in damaged epithelial cells with mesenchymal features. Conclusion: We demonstrated possible evidence to understand the role of SMP30 as a new pivotal factor and the possibility of decreased SMP30 as a potential indicator of EMT at the end stage of CKD.

Key Words:

Chronic kidney disease (CKD) is defined as the presence of structural or functional damage on the kidneys (1, 2). With persistent damage, glomerular sclerosis, tubulo-interstitial inflammation, tubular atrophy, and finally interstitial fibrosis occur (2). Previous studies have reported that CKD is a common cause of death in non-domestic or domestic felidae (3-6). However, only a few studies have reported histopathological cases of CKD in Siberian tigers.

Several previous studies have tried to define critical cells producing excessive amounts of extracellular matrix (ECM) components and how they could be regulated (7). Tubular interstitial fibrosis is induced by on-going chronic inflammation and results in the loss of the kidney’s function and tubular structure. Epithelial–mesenchymal transition (EMT) is one of the causes of fibrosis in the kidney, a process in which epithelial cells change their morphology and functions toward mesenchymal cells (8). EMT is activated by a chronic inflammatory response in the kidney, which results in the secretion of TGF-β1 and the induction of oxidative stress. Constant secretions of pro-EMT molecules such as TGF-β1 may decrease the expression of E-cadherin, resulting in alteration of epithelial cells to a myofibroblast phenotype leading to a fibrotic kidney (9).

SMP30 plays multi-functional roles in cell regulation and is mainly expressed in renal tubular epithelial cells and liver hepatocytes (10-12). SMP30 decreases with age, and its reduction is associated with the downgrading of cellular functions. The expression level of SMP30 was reported to decrease in chronically damaged renal epithelial cells, and the renal epithelial cells that constitute tubules were necrotised and lost their structure (10, 13). A study suggested the possible involvement SMP30 in liver fibrosis (14); however, the role of SMP30 in kidney fibrosis has not been described yet.

Therefore, we investigated two necropsy cases of male Siberian tigers (Panthera tigris altaica). Case 1 died at the age of 12, and case 2 died at the age of 20. Considering that the average life expectancy of tigers is approximately 20-26 years in captivity, these tigers are not considered young (15). In this study, we revealed SMP30 protein expression patterns in the two Siberian tigers with CKD and their relationship with EMT in renal interstitial fibrosis by histopathological methods.

Materials and Methods

Ethical approval. The conducted research was not related to animal use, therefore ethical approval was not required.

Necropsy and sample collection. Two kidney samples from male Siberian tigers (Panthera tigris altaica) were collected at the Department of Veterinary Pathology, Kyungpook National University (Daegu, Republic of Korea). According to the necropsy, both were diagnosed with CKD. Kidney samples were rapidly collected from both cases during necropsy and fixed in 10% neutral formalin.

Histopathological analysis. The fixed tissue samples were dehydrated routinely, embedded in paraffin, and cut into 4 μm thick sections. For the histopathological diagnosis, the sections were stained with hematoxylin and eosin and Masson’s trichrome.

Immunohistochemistry. The ZytoChem Plus (HRP) Broad Spectrum Kit (Cat. No. HRP060, Zytomed Systems, Berlin, Germany) was used for immunohistochemistry. The deparaffinized sections were incubated in Proteinase K (20 μg/ml). For antigen retrieval, they were treated with 3% hydrogen peroxide in methanol for 30 min at room temperature and heated for 30 min in citric acid buffer (6.0 pH). After cooling, the samples were washed with phosphate-buffered saline (PBS) and incubated with a blocking solution (Cat. No. HRP060, Zytomed Systems) for 1 h at room temperature. After blocking, the sections were immunolabelled with the primary antibodies polyclonal rabbit anti-SMP30 (1:100, Cat. No. SML-ROI001-EX, Cosmo Bio Co., Ltd., Tokyo, Japan), monoclonal mouse anti-α-smooth muscle actin (α-SMA; 1:500, Cat. No. M0851, Dako, Glostrup, Denmark), monoclonal mouse anti-vimentin (1:200, Cat. No. MA5-11883, Invitrogen, Waltham, MA, USA), and monoclonal mouse anti-pan-cytokeratin (pan-CK; 1:200, Cat. No. ab86734, Abcam, Cambridge, UK) at 4°C overnight. After washing three times with PBS, sections were incubated with biotinyl secondary antibody polyvalent (Cat. No. HRP060, Zytomed Systems) and streptavidin horseradish peroxidase conjugate (Cat. No. HRP060, Zytomed Systems) for 10 min. The immunohistochemistry expression levels were detected by a DAB (3,3′-diaminobenzidine) substrate kit for peroxidase (Cat. No. SK-4100, Vector Laboratories, Inc., Burlingame, CA, USA). After rinsing in distilled water, they were counterstained with 10% hematoxylin.

Immunofluorescence. For antigen retrieval, sectioned slides were treated with 3% hydrogen peroxide in methanol for 30 min at room temperature and heated for 30 min in citric acid buffer (6.0 pH). After cooling, they were treated with 0.1% Triton X for 20 min. After washing with PBS, 5% donkey serum was used as a blocking solution for 1 h. Then, the sections were immunolabelled with the primary antibodies polyclonal rabbit anti-SMP30 (1:50, Cat. No. SML-ROI001-EX, Cosmo Bio Co., Ltd.), monoclonal mouse anti-α-SMA (1:1,000, Cat. No. M0851, Dako), monoclonal mouse anti-vimentin (1:100, Cat. No. MA5-11883, Invitrogen), monoclonal mouse anti-pan-CK (1:100, Cat. No. ab86734, Abcam) and double-stained polyclonal rabbit anti-pan-CK (1:200, Cat. No. ab9377, Abcam) at 4°C overnight. After washing three times in PBS, the samples were treated with secondary antibodies including donkey anti-mouse IgG Alexa Fluor 488 (1:500; Cat. No. ab150105, Abcam) and donkey anti-rabbit IgG Alexa Fluor 555 (1:500; Cat. No. ab150066, Abcam) for 1 h at room temperature. For nuclei staining, ProLong Gold Antifade Reagent with DAPI (Cat. No. 8961, Cell Signalling, Danvers, MA, USA) was used. An Olympus BX53 fluorescence microscope (Olympus, Tokyo, Japan) was used for visualization.

Results

Gross findings and histopathological analysis of CKD with interstitial renal fibrosis from two necropsied tigers. In the blood tests of case 1, assessed 9 days before death, its blood urea nitrogen level was >50.4 (normal range=6.8-12.2 mmol/l); creatinine, 1,697.3 (normal range=70.7-194.5 μmol/l); and ammonia, 71.7 μmol/l, which indicated pathological damage of the kidneys and renal dysfunction.

Both kidneys, from cases 1 and 2, had a yellow-tan and irregular surface with purulent exudates. In case 1, the cut surface of the kidneys showed yellow inflammatory exudates in the renal pelvis and yellow medulla, which spread to the renal papillae. The cortex was swollen, and petechiae could be seen. The yellow-whitish necrotic area partially involved some renal papillae and medullary pyramids with intramedullary fibrosis (Figure 1A). In case 2, the gross findings included kidney hypertrophy and purulent exudates with hemorrhage. The cut surface showed dilation of the renal pelvis with purulent exudates and partially yellow-whitish necrotic renal papillae with intramedullary fibrosis (Figure 1B). Although the two cases showed different gross features, they commonly had renal intramedullary fibrosis with necrotic renal papillae.

Figure 1.
Figure 1.

Gross features of damaged kidneys and histopathological investigation for renal fibrosis in two Siberian tigers. Hematoxylin and eosin and Masson’s trichrome staining. (A and B) Each cut surface of kidneys showed renal intramedullary fibrosis with necrotic renal papillae (A, case 1; B, case 2). (C and D) Renal fibrosis was present in two tigers with chronic kidney disease. Microscopic findings of a similar pattern of damaged renal tubule and renal interstitial fibrosis (C, case 1; D, case 2). Bar=50 μm (E and F) The collagen fibers of the fibrosis are shown as blue in Masson’s trichrome staining (E, case 1; F, case 2). Bar=50 μm.

Microscopically, dense fibrotic collagen depositions were observed in the renal tubule-interstitial space of the two tigers (Figure 1C and D). Moreover, chronic inflammatory cell infiltrations and hemorrhage were also observed. The number of renal tubules was reduced; however, some renal tubules showed cystic changes. These necrotic tubular epithelial cells detached from the basal membrane and showed atrophy and degeneration (Figure 1C and D). Some of the detached tubular epithelial cells changed their morphology, characterized by stretched cytoplasm linear and lose polarity. Masson’s trichrome staining showed a similar pattern of damage on renal tubules and renal interstitial fibrosis. The collagen fibers were stained blue and replaced the renal tubulo-interstitial space (Figure 1E and F). In case 2, matrix-assisted laser desorption/ionization time-of-flight analysis identified Proteus mirabilis, Enterococcus faecalis and Escherichia coli from kidney tissue (Table I).

View this table:
Table I.

Matrix-assisted laser desorption/ionization time-of-flight-based bacterial identification detected Proteus mirabilis, Enterococcus faecalis and Escherichia coli in the kidney with chronic kidney disease.

Decreased SMP30 expression in renal tubular epithelial cells of the kidneys with CKD. Immunohistochemistry was performed for SMP30 expression in some of the damaged renal tubular epithelial cells (Figure 2A and B). These tubular epithelial cells were detached from the basal membrane and lost their tubular structure. These damaged epithelial cells were positive for pan-CK, suggesting those cells originated from epithelial cells (Figure 2C and D). Generally, SMP30 expressions showed very low level especially in linear shaped epithelial cells compared with those in normal cuboidal or columnar shaped epithelial cells characterized by strong expression levels of SMP30. The morphology of fibroblasts stained with pan-CK, indicates EMT; furthermore, as the expression of SMP30 decreases, the epithelial cell morphology changes, thus losing the EMT characteristics.

Figure 2.
Figure 2.

SMP30 expression patterns and immunoreactivity for pan-cytokeratin on renal tubular epithelial cells, immunohistochemistry. (A) With decreased expression of SMP30, cystic changes on renal tubules are remarkable. Bar=200 μm. (B) Some of the tubular epithelial cells show low or no expression of SMP30, and they are detached from the basement membrane and lose their morphology. Bar=50 μm. (C and D) Tubular epithelial cells show strong immunoreactivity for pan-CK in both cases (C, case 1; D, case 2). Bar=50 μm.

Renal tubular epithelial cells undergoing EMT expressed vimentin but not α-SMA. To evaluate the expression of non-epithelial cell markers in renal tubular epithelial cells, immunohistochemistry was performed for α-SMA and vimentin, which are specific markers of mesenchymal cells (Figure 3A and B). The expression of α-SMA was negative in tubular epithelial cells, but positive only in myofibroblast and interstitial collagen fibers. Some of the tubular epithelial cells were positively stained for vimentin (Figure 3C and D). These damaged tubular epithelial cells showed strong vimentin expression similar with those of interstitial fibroblasts. These cells were stretched linearly and detached from the basal membrane and acquired the appearance of mesenchymal-like cells.

Figure 3.
Figure 3.

Immunoreactivity for α-smooth muscle actin (α-SMA) and vimentin in renal tubular epithelial cells, immunohistochemistry. (A and B), Interstitial fibroblast and collagen fibers show α-SMA immunoreactivity around the tubular epithelial cells, but not in tubular epithelial cells (A, case 1; B, case 2). Bar=50 μm. (C and D) However, some of the tubular epithelial cells show immunoreactivity for vimentin similar to that of mesenchymal cells (C, case 1; D, case 2). Bar=50 μm.

Pan-cytokeratin showed similar expression patterns with those of SMP30 in tubular epithelial cells. Immunofluorescence was performed to evaluate the differences in the expression levels of SMP30 and pan-CK. Pan-CK was expressed in all tubular epithelial cells and several cells co-localized with SMP30 (Figure 4, arrow). However, some of the damaged tubular epithelial cells showed much lower expression levels of SMP30 (Figure 4, arrowhead). These cells exhibited many features of mesenchymal cells such as stretched and linear appearance compared with those of SMP30-positive tubular epithelial cells. These results indicated that SMP30 expression showed a similar pattern with pan-CK, and the expression levels of SMP30 and pan-CK decreased as the tubular epithelial cells lost their own epithelial characteristics.

Figure 4.
Figure 4.

Immunofluorescent microscopy analysis for pan-cytokeratin (pan-CK) and SMP30. Tubular epithelial cells show immunoreactivity for pan-CK (green). Some of the tubular epithelial cells show immunoreactivity for SMP30 (red). Pan-CK/SMP30 double-labelled tubular epithelial cells show normal epithelial cell morphology (arrow). Some of pan-CK-positive tubular epithelial cells show low or no expression of SMP30, and linear morphology (arrowhead). Bar=50 μm.

Tubular epithelial cells with decreased SMP30 expression showed increased expression of vimentin. To evaluate the correlation of mesenchymal cell markers and SMP30, immunofluorescence was performed to detect both α-SMA and vimentin simultaneously in single cells. In renal tubular epithelial cells, SMP30 was not expressed in cells that highly expressed α-SMA and vimentin (Figure 5 and Figure 6). No tubular epithelial cells were positive for α-SMA; only collagen fibers and myofibroblasts were positive for α-SMA. However, vimentin was expressed in some tubular epithelial cells around the nuclei (Figure 6). These vimentin-positive epithelial cells were stretched or detached from the basement membrane.

Figure 5.
Figure 5.

Immunofluorescent microscopy analysis for α-smooth muscle actin (α-SMA) and SMP30. Immunofluorescence for α-SMA (green). No immunoreactivities for α-SMA are observed in tubular epithelial cells. Immunofluorescence for SMP30 (red). No expression for SMP30 is observed in α-SMA-positive cells. Bar=50 μm.

Figure 6.
Figure 6.

Immunofluorescent microscopy analysis for vimentin and SMP30. Immunofluorescence for vimentin (green). Immunofluorescence for SMP30 (red). No expression of SMP30 is observed in vimentin-positive cells. Immunoreactivities for vimentin are observed around the tubular epithelial cell nuclei and no colocalization with vimentin and SMP30 is observed. Bar=50 μm.

EMT in renal tubular cells of the kidneys with CKD and the relationship with SMP30. In immunofluorescence using vimentin (green) and pan-CK (red), double-positive expression was found in some of the tubular epithelial cells (Figure 7A). Pan-CK was expressed in the cytoplasm, and vimentin was expressed around the nuclei in these cells. These results suggest the presence of EMT in these cells because relevant markers were expressed simultaneously only in damaged epithelial cells with mesenchymal features. Moreover, the expression of vimentin increased whereas the expression of SMP30 and pan-CK decreased in these cells (Figure 7B).

Figure 7.
Figure 7.

Immunofluorescence analysis for vimentin and pan-cytokeratin (pan-CK) and the epithelial–mesenchymal (EMT) score. (A) Immunofluorescence for vimentin (green). Immunofluorescence for pan-CK (red). Vimentin/pan-CK double-labelled tubular epithelial cells are shown with arrows. While the expression of vimentin increased, the expression of pan-CK decreased within the cytoplasm of damaged tubular epithelial cells when transforming into mesenchymal cells. Bar=50 μm. (B) EMT score (EMT relative proportion: spindle cells/non-spindle cells) in the renal tubular epithelium of tigers with chronic kidney disease. As the EMT score increases, the expression level of vimentin increases, whereas the expression levels of SMP30 and pan-CK decrease.

Discussion

It is unclear which cell types produce ECM in fibrosis. EMT is one of the leading causes of fibrosis in the kidney, lung, liver, and intestine (16). Many studies have suggested the presence EMT in CKD animal models including diabetic nephropathy, glomerulonephritis, and chronic allograft tubulo-interstitial fibrosis (17-19). In a previous study, Nupr1 induced collagen production and renal fibrosis through myofibroblast transdifferentiation from tubular epithelial cells (20). Among the three types of EMT, type 2 EMT is associated with the repair of injured tissues associated with trauma and inflammation that activated the transition into fibroblasts and other related cells to rebuild tissue structures. In the presence of persistent injuries, fibrotic destruction occurs (7, 8).

In this study, decreased SMP30 expression in damaged renal tubular epithelial cells with interstitial fibrosis was observed in two Siberian tigers. In the microscopic analysis, severe fibrotic collagen deposition was found in the renal tubulo-interstitial space along with cystic changes in renal tubules. Moreover, the degeneration of renal tubular epithelial cells indicates gradual loss of renal function, leading to the terminal stage of CKD (2). These damaged renal tubular epithelial cells are characterized by weak or absence of SMP30 expression.

Even if the main role of SMP30 is unknown, a decreased SMP30 expression was observed in older, damaged kidneys and end stage renal disease states such as diabetic nephropathy (13, 21, 22). With persistent damage, renal tubular epithelial cells show decreasing levels of SMP30 expression, which appear to exacerbate CKD and cause a change in their morphology. These modified renal tubular epithelial cells lost their polarity and detached from the basement membrane, changing to mesenchymal-like cells. Double staining enabled us to show the mesenchymal morphology of pan-CK-positive tubular epithelial cells, and a decreased SMP30 expression alters the morphology of epithelial cells, which results in the loss of their properties and leads to EMT.

As the expression of SMP30 decreased, the expression of vimentin increased. The expression of the mesenchymal cell markers such as vimentin could be observed by myofibroblast differentiation in the diseased kidney (23-25). The vimentin expression pattern is critical evidence for the EMT, which could be found in cancers, such as breast cancer and squamous cell carcinoma (26-28).

However, the current study lacks enough samples to further understand the regulatory role of SMP30 in EMT. Therefore, further studies are needed to demonstrate the clear role of SMP30 in the EMT of tiger CKD.

Conclusion

In our results, the vimentin-positive renal tubular epithelial cells had low or absence of SMP30 expression and changed their morphology as mesenchymal-like cells. Furthermore, vimentin and pan-CK expression were observed in the double staining experiment using renal tubular epithelial cells, which proposed EMT in renal interstitial fibrosis.

This important finding suggests that CKD causes functional and morphological modifications in renal tubular epithelial cells and a decreased SMP30 expression may play a key role in EMT and renal interstitial fibrosis. In conclusion, decreased SMP30 expression could stimulate EMT and cause severe renal interstitial fibrosis at the end stage of CKD in Siberian tigers. We present SMP30 as a new indicator of EMT signaling.

Acknowledgements

This work was supported by the Korea Arboreta and Gardens Institute affiliated organization Baekdudaegan National Arboretum, Siberian Tiger Conservation center.

Footnotes

  • Authors’ Contributions

    YRJ and JHY were involved in data curation, formal analysis, investigation, methodology, visualization, and wrote the original manuscript. YJL, SBL, and SYH participated in the investigation. SGB, KTK, YSK, and SJP helped with experimental methodology. JKP and THK supervised the investigation, were involved in the conceptualization, and reviewed and revised the manuscript. All Authors read and approved the final manuscript.

  • Conflicts of Interest

    The Authors declare that they have no competing interests in relation to this study.

  • Received August 2, 2023.
  • Revision received September 14, 2023.
  • Accepted September 15, 2023.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Decreased SMP30 Expression Is Related With EMT in the Kidneys of Two Siberian Tigers With CKD
YI-RANG JUNG, JAE-HYUK YIM, YOUNG-JIN LEE, SAE-BOM LEE, SUNG-YONG HEO, SEUL-GI BAE, KYOO-TAE KIM, YOUNG-SAM KWON, SANG-JOON PARK, JIN-KYU PARK, TAE-HWAN KIM
In Vivo Jan 2024, 38 (1) 226-234; DOI: 10.21873/invivo.13429
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