Glomerular endothelial cell-podocyte stresses and crosstalk in structurally normal kidney transplants

Menon, Rajasree; Berthier, Céline C.; Nair, Viji; Farkash, Evan A.; Hodgin, Jeffrey B.; Yang, Yong; Luo, Jinghui; Woodside, Kenneth J.; Zamani, Haniyeh; Norman, Silas P.; Wiggins, Roger C.; Kretzler, Matthias; Naik, Abhijit S.

doi:10.1016/j.kint.2021.11.031

Cited by 16 publications

(8 citation statements)

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“…In fact, diminution of WT1, an established marker of podocytes, has been associated with loss of prominent barrier functions (53) and early changes towards glomerulosclerosis (54), while enhanced TUNEL signals stood for apoptosis or repair stages (55). Key podocyte genes such as palladin, CD2AP, synaptopodin, nephronectin, and podocalyxin, all intrinsic structural components of podocytes, were selectively downregulated in Tac which also underscores higher podocyte damage compared to CsA, and concomitant impairment in shape and motility of their foot processes (56,57). Associated decrease in phosphorylation of CD2AP, a stabilizing protein of the slit diaphragm, at Ser 404 may reflect further loss of function (58).…”

Section: Discussionmentioning

confidence: 97%

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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Section: Discussionmentioning

confidence: 97%

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

Demirci

Popović

Dittmayer

et al. 2023

Preprint

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“…The foot process extensions that attach podocytes to the basement membrane combine with those of neighboring podocytes to form the ultimate filtration barrier of the glomerulus. This filtration barrier is a unique cellular junction formed from podocyte-specific proteins (nephrin and synaptopodin), which interact with the actin cytoskeleton [29]. Foot process effacement with subsequent podocyte detachment, a crucial step connected to the occurrence of severe proteinuria, can be caused by molecular events that disrupt the integrity of the actin cytoskeleton [30].…”

Section: Discussionmentioning

confidence: 99%

C/EBPβ isoform‐specific regulation of podocyte pyroptosis in lupus nephritis‐induced renal injury

Zou,

Chen,

Wang

et al. 2023

The Journal of Pathology

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As an essential factor in the prognosis of systemic lupus erythematosus (SLE), lupus nephritis (LN) can accelerate the rate at which patients with SLE can transition to chronic kidney disease or even end‐stage renal disease. Podocytes now appear to be a possible direct target in LN in addition to being prone to collateral damage from glomerular capillary lesions induces by immune complexes and inflammatory processes. The NLRP3 inflammasome is regulated by CCAAT/enhancer‐binding protein β (C/EBPβ), which is involved in the pathogenesis of SLE. However, the role and mechanism of C/EBPβ in LN remain unclear. In this investigation, glomerular podocytes treated with LN serum and MRL/lpr mice were employed as in vivo and in vitro models of LN, respectively. In vivo, the expression of C/EBPβ isoforms was detected in kidney specimens of humans and mice with LN. Then we assessed the effect of C/EBPβ inhibition on renal structure and function by injecting RNAi adeno‐associated virus of C/EBPβ shRNA into MRL/lpr mice. In vitro, glomerular podocytes were treated with LN serum and C/EBPβ siRNA to explore the role of C/EBPβ in the activation of the AIM2 inflammasome and podocyte injury. C/EBPβ‐LAP and C/EBPβ‐LIP were significantly overexpressed in kidney tissue samples from LN patients and mice, and C/EBPβ inhibition significantly alleviated renal function damage and ameliorated renal structural deficiencies. Inflammatory pathways downstream from the AIM2 inflammasome could be suppressed by C/EBPβ knockdown. Furthermore, the upregulation of C/EBPβ‐LAP could activate the AIM2 inflammasome and podocyte pyroptosis by binding to the promoters of AIM2 and CASPASE1 to enhance their expression, and the knockdown of AIM2 or (and) caspase‐1 reversed the effects of C/EBPβ‐LAP overexpression. Interestingly, C/EBPβ‐LIP overexpression could transcriptionally inhibit IRAG and promote Ca2+ release‐mediated activation of the AIM2 inflammasome. This finding suggests that C/EBPβ is not only involved in the regulation of the expression of key proteins of the AIM2 inflammasome but also affects the polymerization of key proteins of the AIM2 inflammasome through the regulation of Ca2+ release. In conclusion, this study provides a new idea for studying the regulatory mechanism of C/EBPβ and provides a theoretical basis for the early diagnosis and treatment of LN in the future. © 2023 The Pathological Society of Great Britain and Ireland.

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“…The characteristics of the living donor cohort have been described previously. 29 Methods for tissue processing and RNAseq analyses have been previously published. 30 We compared DISP1 and TLR5 expression between AKI and no AKI biopsy tissue on the basis of a Bonferroni-corrected P value adjusted for all the features in the analysis.…”

Section: Methodsmentioning

confidence: 99%

“…Owing to this, we tested whether the combination of these two variants in a compound heterozygosity association analysis strengthens estimates for AKI. Considering the directly genotyped data, we found that logistic regression tests modeling the combined burden of minor alleles for each variant showed stronger associations for AKI (P value 5 1.77310 29 ) than each variant independently (Table 3). In addition, testing the residuals of one variant's association with AKI with the other variant led both variants to remain significant (P values 5 0.001 and 0.0002) (Supplemental Figure 3 and Supplemental Table 5).…”

Section: Compound Heterozygosity and Variant Association Independence...mentioning

confidence: 97%

Genome-wide Association Study for AKI

et al. 2023

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Background: While common genetic risks for chronic kidney disease are well established, genetic factors influencing risk for acute kidney injury (AKI) in hospitalized patients are poorly understood. Methods: We conducted a genome-wide association study in 1,369 participants in the Assessment, Serial Evaluation, and Subsequent Sequelae of AKI (ASSESS-AKI) Study; a multi-ethnic population of hospitalized participants with and without AKI matched on demographics, comorbidities and kidney function prior to hospitalization. We then completed functional annotation of top-performing variants for AKI using single cell RNA sequencing data from kidney biopsies in 12 AKI patients and 18 healthy living donors from the Kidney Precision Medicine Project (KPMP). Results: No genome-wide significant associations with AKI risk were found in ASSESS-AKI (p < 5 x 10 -8 ). The top two variants with the strongest association with AKI mapped to the dispatched RND transporter family member 1 (DISP1) gene and toll like receptor 5 (TLR5) gene locus, rs17538288 (OR=1.55, 95% CI:1.32-182, p=9.47 x 10 -8 ) and rs7546189 (OR=1.53, 95% CI:1.30-1.81, p=4.60 x 10 -7 ). In comparison to kidney tissue from healthy living donors, kidney biopsies in patients with AKI showed differential DISP1 expression in proximal tubular epithelial cells (adjusted p=3.9 x 10-2) and thick ascending limb of the loop of Henle (TAL) (adjusted p=8.7 x 10-3) and differential TLR5 gene expression in TAL (adjusted p=4.9 x 10-30). Conclusions: AKI is a heterogeneous clinical syndrome with various underlying risk factors, etiologies and pathophysiology that may limit the identification of genetic variants. While no variants reached genome wide significance, we report two variants in the intergenic region between DISP1 and TLR5, suggesting this region as a novel risk for AKI susceptibility.

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Glomerular endothelial cell-podocyte stresses and crosstalk in structurally normal kidney transplants

Cited by 16 publications

References 50 publications

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

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

C/EBPβ isoform‐specific regulation of podocyte pyroptosis in lupus nephritis‐induced renal injury

Genome-wide Association Study for AKI

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