PXD038546 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Comparing nephrotoxicity of the calcineurin inhibitors, cyclosporine A and tacrolimus, identifies their differential effects within the renal compartments |
Description | Chronic calcineurin inhibitor (CNI) nephrotoxicity is a major drawback in current immunosuppressive regimens. Pathology includes vascular and tubulointerstitial alterations. Although still commonly in use, cyclosporine A (CsA) is increasingly exchanged for tacrolimus (Tac) for a more favorable clinical outcome. Data on their differential pathogenetic effects in the kidney are, however, still scarce. We asked how CsA and Tac may affect adverse renal responses differentially. Methods- Wistar rats were divided into groups receiving cyclosporineÊ AÊ (n=4, target trough plasma level 3 mg/ml) and the respective vehicle (n=4, saline), or tacrolimus (Tac, FK506, n= 6, target trough plasma level 3.5 ng/ml) and the respective vehicle (n=6, DMSO/PEG500), via subcutaneously implanted osmotic minipumps for 28 days. Clinical parameters from plasma and urine samples were controlled. Animals were prepared for high-end morphological analysis, elective immunostaining, and high-throughput technology. Large scale electron microscopy (EM), confocal, stimulated emission-depletion (STED) and 3D-structured illumination (SIM) microscopy were used for pathology. Protein biochemistry, transcriptome, proteome, and phosphoproteome technologies were used to identify gene expressional differences. Results - In rats, CsA and Tac produced common as well as distinct alterations in glomeruli and tubulointerstitium. Both drugs caused cortical fibrotic foci with sclerotic glomeruli and damaged tubules. With CsA, glomerular damage was milder than with Tac. Proximal tubules showed widespread dysmorphic lysosomes with peripheral LAMP1 signal as well as autophagic and mitophagic vacuoles along with high apoptosis rate and diminished albumin uptake; megalin-dependent endocytosis was causally involved in the changes, and lysosomal exocytosis was sharply stimulated at the luminal cell pole. KIM1 signal was moderate. With Tac, these changes were far less pronounced, but the incidence of focal tubular necrosis along with intense KIM-1 signal was high. High throughput analysis showed differential changes between CsA and Tac with almost no overlap between the respective spectra. CsA caused upregulation of components of the unfolded protein response and apoptosis, whereas Tac resulted in RAS-associated stimulation and vascular deterioration. Conclusions- CNI nephrotoxicity presented with widely differing pathogenetic characteristics upon chronical CsA vs. Tac treatments. Beyond its known vascular effects, CsA markedly affected proximal tubular integrity, whereas Tac was primarily affecting vascular/glomerular components. Both medications produced comparable degrees of nephron loss and fibrosis. Results may serve to better adjust immunosuppressive treatment combinations in transplant patients. |
HostingRepository | PRIDE |
AnnounceDate | 2024-10-22 |
AnnouncementXML | Submission_2024-10-22_06:51:25.011.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Marieluise Kirchner |
SpeciesList | scientific name: Rattus norvegicus (Rat); NCBI TaxID: 10116; |
ModificationList | phosphorylated residue; monohydroxylated residue; deamidated residue |
Instrument | Q Exactive HF-X |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2022-12-05 03:03:36 | ID requested | |
1 | 2024-07-25 09:50:53 | announced | |
⏵ 2 | 2024-10-22 06:51:28 | announced | 2024-10-22: Updated project metadata. |
Publication List
10.1111/apha.14190; |
Demirci H, Popovic S, Dittmayer C, Yilmaz DE, El-Shimy IA, M, ü, lleder M, Hinze C, Su M, Mertins P, Kirchner M, Osmanodja B, Paliege A, Budde K, Amann K, Persson PB, Mutig K, Bachmann S, Immunosuppression with cyclosporine versus tacrolimus shows distinctive nephrotoxicity profiles within renal compartments. Acta Physiol (Oxf), 240(8):e14190(2024) [pubmed] |
Keyword List
submitter keyword: Kidney,Calcineurin, Cyclosporine A, Nephrotoxicity, Rat, Tacrolimus, Phosphoproteome |
Contact List
Philipp Mertins |
contact affiliation | Max-Delbrueck Center, Berlin Institute of Health (BIH), Berlin, Germany |
contact email | philipp.mertins@mdc-berlin.de |
lab head | |
Marieluise Kirchner |
contact affiliation | Proteomics Platform, BIH@Charite |
contact email | marieluise.kirchner@mdc-berlin.de |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD038546
- Label: PRIDE project
- Name: Comparing nephrotoxicity of the calcineurin inhibitors, cyclosporine A and tacrolimus, identifies their differential effects within the renal compartments