Automated image analysis of a glomerular injury marker desmin in spontaneously diabetic Torii rats treated with losartan

Kakimoto, Tetsuhiro; Okada, Kinya; Hirohashi, Yoshihiro; Relator, Raissa; Kawai, Mizue; Iguchi, Taku; Fujitaka, Keisuke; Nishio, Masafumi; Kato, Tsuyoshi; Fukunari, Atsushi; Utsumi, Hiroyuki

doi:10.1530/joe-14-0164

Cited by 42 publications

(34 citation statements)

References 18 publications

(38 reference statements)

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“…Conversely, in the control group, FPE demonstrated no significant changes until 25 weeks. Furthermore, we evalu- ated the expression of desmin, a known marker of podocyte injury [18,19], whose increased expression during podocyte injury was shown in a model leading to FSGS [18]. In this study, desmin showed increased expression compared with the control group from 2 weeks on CsA treatment (p < 0.05; Fig.…”

Section: Timing Relationship Between Pec Activation and Podocyte Injurymentioning

confidence: 65%

CD44-Positive Glomerular Parietal Epithelial Cells in a Mouse Model of Calcineurin Inhibitors-Induced Nephrotoxicity

Hayashi¹,

Okamoto²,

Yamazaki³

et al. 2019

Nephron

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Background/Aims: Calcineurin inhibitors (CNIs) such as cyclosporine A (CsA) and tacrolimus are immunosuppressants that are frequently used as “key drugs” in the fields of transplantation, steroid resistance, refractory nephrotic syndrome, and autoimmune disease. However, long-term CNI use causes nephrotoxicity, the features of which are arteriolar hyalinosis, tubular atrophy, striped interstitial fibrosis, and focal segmental glomerulosclerosis (FSGS). We investigated whether FSGS in CNI-induced nephrotoxicity is associated with CD44-positive glomerular parietal epithelial cells (PECs), which play a significant role in experimental and human FSGS pathogenesis. Methods: We utilized the mouse model of CsA-induced nephrotoxicity, as well as controls. Histopathological and functional data were sequentially collected from 1 to 25 weeks after CsA injection. Glomerular expression of CD44 was immunohistochemically evaluated, as were markers for glomerular podocytes and PECs. Results: Glomerular CD44 expression occurred from 2 weeks after CsA injection and gradually increased in the CsA group. CD44-positive glomerular cells showed coexpression of claudin-1 (PEC marker) but not of synaptopodin (podocyte marker). From 20 weeks after CsA injection, the cells formed a bridge between Bowman’s capsule and the capillary tuft. These features are compatible with those of activated PECs, in which increased foot process effacement leads to bridge formation, and subsequently to an increase in glomerulosclerosis and a decrease in the expression of podocyte markers from 20 weeks. Conclusion: CD44-positive (activated) PECs reflect extremely early podocyte injury in the progression of FSGS formation and may be a good marker for early detection of CNI-induced nephrotoxicity.

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Section: Timing Relationship Between Pec Activation and Podocyte Injurymentioning

confidence: 65%

CD44-Positive Glomerular Parietal Epithelial Cells in a Mouse Model of Calcineurin Inhibitors-Induced Nephrotoxicity

Hayashi¹,

Okamoto²,

Yamazaki³

et al. 2019

Nephron

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“…There is evidence that desmin also connects the sarcomere to the ECM through desmosomes which is likely important in signaling between the ECM and the sarcomere in regulating tissue contraction and movement [41]. Of note, prior studies suggest that desmin is a sensitive marker of podocyte injury [43]. Also, desmin mRNA and protein are increased in cultured mouse podocytes and in vivo study it has been reported that desmin is increased in damaged mouse podocytes by insults of numerous kidney disorders, suggesting that desmin is involved in podocyte injury [44, 45].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of TRPC6 Signal Pathway Alleviates Podocyte Injury Induced by TGF-β1

Huang

You

Lin

et al. 2017

Cell Physiol Biochem

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Background/Aims: Transforming growth factor beta 1 (TGF-β1) plays a critical role in the pathogenesis of glomerulosclerosis. The purpose of this study was to examine the effects of inhibition of transient receptor potential cation channel C6 (TRPC6) on podocyte injury induced by TGF-β1 via nephrin and desmin mechanisms. Methods: A rat model of nephropathy was first induced by intravenous injections of adriamycin to determine TRPC6 signal pathway engaged in glomerulosclerosis in vivo. Conditionally immortalized podocytes were cultured in vitro and they were divided into four groups: control; TGF-β1 treatment; TGF-β1 with TRPC6 knockdown and TGF-β1 without TRPC6 knockdown. Real time RT-PCR and Western blot analysis were employed to determine the mRNA and protein of expression of nephrin, desmin and caspase-9, respectively. Flow cytometry was used to examine the apoptotic rate of podocytes and DAPI fluorescent staining was used to determine apoptotic morphology. Results: In vivo experiment, adriamycin significantly upregulated the protein expression of TGF-β1, TRPC6, desmin and caspase-9, and decreased nephrin. Consistent with the latter results, in vitro experiment mRNA and protein expression of desmin and caspase-9 was increased in cultured TGF-β1-treated podocytes, whereas nephrin was declined as compared with the control group. Importantly, TRPC6 knockdown significantly attenuated the upregulated desmin and caspase-9, and alleviated impairment of nephrin induced by TGF-β1. Moreover, typical morphologic features were presented in apoptotic podocytes. The number of apoptotic podocytes was increased after exposure to TGF-β1 and this was alleviated after TRPC6 knockdown. TRPC6 knockdown also decreased an apoptosis rate of TGF-β1-treated podocytes. Note that negative TRPC6 transfection control failed to alter an increase of the apoptosis rate in TGF-β1-treated podocytes. Conclusions: TGF-β1 induced by glomerulosclerosis impairs the protein expression of nephrin and amplifies the protein expression of desmin and caspase -9 via TRPC6 signal pathway. Inhibition of TRPC6 alleviates these changes in podocytes-treated with TGF-β1 and attenuated apoptosis of podocytes. Our data suggest that TRPC6 signal plays an important role in mediating TGF-β1-induced podocyte injury via nephrin, desmin and caspase-9. Results of the current study also indicate that blocking TRPC6 signal pathway has a protective effect on podocyte injury. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of podocyte injury observed in glomerulosclerosis.

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“…There is evidence that desmin also connects the sarcomere to the ECM through desmosomes which is likely important in signaling between the ECM and the sarcomere in regulating tissue contraction and movement [32]. Of note, prior studies suggest that desmin is a sensitive marker of podocyte injury [34]. Also, desmin mRNA and protein are increased in cultured mouse podocytes and in vivo study it has been reported that desmin is increased in damaged mouse podocytes by insults of numerous kidney disorders, suggesting that desmin is involved in podocyte injury [35, 36].…”

Section: Discussionmentioning

confidence: 99%

Role of Protease-Activated Receptor 2 in Regulating Focal Segmental Glomerulosclerosis

Wang

et al. 2017

Cell Physiol Biochem

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Background /Aims: The underlying mechanisms leading to focal segmental glomerulosclerosis (FSGS) are lacking. In this report, we examined the role of protease-activated receptors (PARs) subtype PAR2 and its downstream signals in regulating the pathophysiological process of FSGS. Methods: Nephropathy was induced by intravenous injections of adriamycin (ADR) in rats to study FSGS. Western Blot analysis and ELISA were employed to determine the protein expression levels of PAR2 and its downstream signal pathways as well as the levels of PICs. Results: In ADR rats, expression of PAR2, PKCε and PKA was amplified and this was accompanied with increases of pro-inflammatory cytokines (PICs) including IL-1β, IL-6 and TNF-α. Inhibition of PAR2 signal by systemic administration of FSLLRY-NH2 (FSL) attenuated amplification of PICs. Notably, FSL further influenced key molecular mediators during development of FSGS. i.e., it specifically restored the impaired nephrin and attenuated the exaggerated transforming growth factor beta 1 (TGF-β1), caspase-9 and desmin thereby improving worsened renal functions and glomerular injury. Consistent with this, in cultured podocytes FSL also largely restored downregulation of nephrin and attenuated amplifications of caspase-9 and desmin induced by TGF-β1. Conclusions: Results of this study suggest that PAR2 plays an important role in mediating renal injury induced by glomerulosclerosis. Inhibition of PAR2 signal pathway has a protective effect on FSGS mainly via PIC and TGF-β1 mechanisms. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of FSGS observed in patients.

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Automated image analysis of a glomerular injury marker desmin in spontaneously diabetic Torii rats treated with losartan

Cited by 42 publications

References 18 publications

CD44-Positive Glomerular Parietal Epithelial Cells in a Mouse Model of Calcineurin Inhibitors-Induced Nephrotoxicity

CD44-Positive Glomerular Parietal Epithelial Cells in a Mouse Model of Calcineurin Inhibitors-Induced Nephrotoxicity

Inhibition of TRPC6 Signal Pathway Alleviates Podocyte Injury Induced by TGF-β1

Role of Protease-Activated Receptor 2 in Regulating Focal Segmental Glomerulosclerosis

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