Influence of cyclosporine A on glomerular growth and the effect of mizoribine and losartan on cyclosporine nephrotoxicity in young rats

Kim, Ji Eun; Lee, Yeon Hee; Lim, Beom Jin; Jeong, Hyeon Joo; Kim, Pyung Kil; Smıth, Lee

doi:10.1038/srep22374

Cited by 4 publications

(4 citation statements)

References 34 publications

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“…However, critical challenges to allogeneic islet transplantation include an unsolved regulatory framework ( 19 ), early loss of transplanted islets from instant blood-mediated inflammatory reaction ( 20 , 21 ), and the need for life-long immunosuppression to protect the islet grafts from allo- and autoimmunity. Immunosuppression causes most side effects, including β cell toxicity ( 22 ), kidney toxicity ( 23 , 24 ), infections ( 25 ), and cancer ( 26 ), and limits the more widespread use of this strategy. We here report the concept of human allogeneic, gene-engineered hypoimmune (HIP) islets for transplantation without the need for immunosuppression.…”

Section: Introductionmentioning

confidence: 99%

Human hypoimmune primary pancreatic islets avoid rejection and autoimmunity and alleviate diabetes in allogeneic humanized mice

Gattis

Olroyd

et al. 2023

Sci. Transl. Med.

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Transplantation of allogeneic pancreatic donor islets has successfully been performed in selected patients with difficult-to-control insulin-dependent diabetes and impaired awareness of hypoglycemia (IAH). However, the required systemic immunosuppression associated with this procedure prevents this cell replacement therapy from more widespread adoption in larger patient populations. We report the editing of primary human islet cells to the hypoimmune HLA class I– and class II–negative and CD47-overexpressing phenotype and their reaggregation into human HIP pseudoislets (p-islets). Human HIP p-islets were shown to survive, engraft, and ameliorate diabetes in immunocompetent, allogeneic, diabetic humanized mice. HIP p-islet cells were further shown to avoid autoimmune killing in autologous, diabetic humanized autoimmune mice. The survival and endocrine function of HIP p-islet cells were not impaired by contamination of unedited or partially edited cells within the p-islets. HIP p-islet cells were eliminated quickly and reliably in this model using a CD47-targeting antibody, thus providing a safety strategy in case HIP cells exert toxicity in a future clinical setting. Transplantation of human HIP p-islets for which no immunosuppression is required has the potential to lead to wider adoption of this therapy and help more diabetes patients with IAH and history of severe hypoglycemic events to achieve insulin independence.

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Section: Introductionmentioning

confidence: 99%

Human hypoimmune primary pancreatic islets avoid rejection and autoimmunity and alleviate diabetes in allogeneic humanized mice

Gattis

Olroyd

et al. 2023

Sci. Transl. Med.

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“…In conjunction with fibrous podocyte synechiae and CD45‐positive inflammatory cell accumulations these features suggested early stages of sclerotic lesions 48,49 . Tuft retraction, likely resulting from diminished microvascular perfusion, 50 and decreased FSD occurred to similar extent in CsA and Tac. Proteinuria was still not detected, which may be related with the decrease in GFR; also, podocyte albumin storage was strongly decreased in CNI, pointing at its reduced filtration (not shown).…”

Section: Discussionmentioning

confidence: 88%

Immunosuppression with cyclosporine versus tacrolimus shows distinctive nephrotoxicity profiles within renal compartments

Demirci,

Popovic,

Dittmayer

et al. 2024

Acta Physiologica

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AimCalcineurin inhibitors (CNIs) are the backbone for immunosuppression after solid organ transplantation. Although successful in preventing kidney transplant rejection, their nephrotoxic side effects contribute to allograft injury. Renal parenchymal lesions occur for cyclosporine A (CsA) as well as for the currently favored tacrolimus (Tac). We aimed to study whether chronic CsA and Tac exposures, before reaching irreversible nephrotoxic damage, affect renal compartments differentially and whether related pathogenic mechanisms can be identified.MethodsCsA and Tac were administered chronically in wild type Wistar rats using osmotic minipumps over 4 weeks. Functional parameters were controlled. Electron microscopy, confocal, and 3D‐structured illumination microscopy were used for histopathology. Clinical translatability was tested in human renal biopsies. Standard biochemical, RNA‐seq, and proteomic technologies were applied to identify implicated molecular pathways.ResultsBoth drugs caused significant albeit differential damage in vasculature and nephron. The glomerular filtration barrier was more affected by Tac than by CsA, showing prominent deteriorations in endothelium and podocytes along with impaired VEGF/VEGFR2 signaling and podocyte‐specific gene expression. By contrast, proximal tubule epithelia were more severely affected by CsA than by Tac, revealing lysosomal dysfunction, enhanced apoptosis, impaired proteostasis and oxidative stress. Lesion characteristics were confirmed in human renal biopsies.ConclusionWe conclude that pathogenetic alterations in the renal compartments are specific for either treatment. Considering translation to the clinical setting, CNI choice should reflect individual risk factors for renal vasculature and tubular epithelia. As a step in this direction, we share protein signatures identified from multiomics with potential pathognomonic relevance.

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“…In conjunction with fibrous podocyte synechiae and CD45-positive cell accumulations these features suggested early stages of sclerotic lesions and onset of inflammation (43,44). Tuft retraction, likely resulting from diminished microvascular perfusion (45), and decreased FSD occurred to similar extent in CsA and Tac, whereas reduced endothelial fenestration was found more in Tac than in CsA. Early work has reported loss of pore density and fenestral size also in a CsA rat model (46).…”

Section: Discussionmentioning

confidence: 90%

Immunosuppression with Cyclosporine versus Tacrolimus shows distinctive nephrotoxicity profiles within renal compartments

Demirci

Popović

Dittmayer

et al. 2023

Preprint

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Calcineurin inhibitors (CNI) are the backbone for immunosuppression after solid organ transplantation. Although successful in preventing kidney transplant rejection, their nephrotoxic side effects notoriously contribute to allograft injury despite attempts to optimize their application, often with additional medications. The etiology of chronic renal parenchymal changes is complex irrespective of chosen therapy with either cyclosporine A (CsA) or currently favoured tacrolimus (Tac). The pathogenetic detail of their respective toxicities has not been fully understood. To test whether CsA and Tac cause adverse renal responses differentially, we employed a chronic rat model with continous drug application. Histopathology of the renal compartments was combined with multiomics analysis. Both drugs caused significant albeit differential damage in vasculature and nephron. The glomerular filtration barrier was more affected by Tac than by CsA, showing prominent deteriorations in pore endothelium and podocytes along with impaired VEGF/VEGFR2 signaling and podocyte-specific gene expression. By contrast, proximal tubule epithelia were more severely affected by CsA than by Tac, revealing lysosomal dysfunction and enhanced apoptosis along with impaired proteostasis and oxidative stress. We conclude that pathogenetic alterations in renal microenvironments are specific for either treatment. We have identified related biomarkers to adequately address chronic CNI nephropathy in transplant recipients.

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Influence of cyclosporine A on glomerular growth and the effect of mizoribine and losartan on cyclosporine nephrotoxicity in young rats

Cited by 4 publications

References 34 publications

Human hypoimmune primary pancreatic islets avoid rejection and autoimmunity and alleviate diabetes in allogeneic humanized mice

Human hypoimmune primary pancreatic islets avoid rejection and autoimmunity and alleviate diabetes in allogeneic humanized mice

Immunosuppression with cyclosporine versus tacrolimus shows distinctive nephrotoxicity profiles within renal compartments

Immunosuppression with Cyclosporine versus Tacrolimus shows distinctive nephrotoxicity profiles within renal compartments

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