Analysis of the human kidney transcriptome and plasma proteome identifies markers of proximal tubule maladaptation to injury

Wen, Yumeng; Su, Emily; Xu, Leyuan; Menez, Steven; Moledina, Dennis G.; Obeid, Wassim; Palevsky, Paul M.; Mansour, Sherry G.; Devarajan, Prasad; Cantley, Lloyd G.; Cahan, Patrick; Parikh, Chirag R.; ,; ,

doi:10.1126/scitranslmed.ade7287

Cited by 3 publications

(1 citation statement)

References 61 publications

(100 reference statements)

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“…Scientists are also promoting the discovery of new treatments and targets for various types of nephritis (76-79). Indeed, integrating transcriptomics with other omics can further advance the discovery of novel mechanisms and biomarkers for renal diseases (80). Therefore, we leveraged transcriptomic data from IgA nephropathy and lupus nephritis to elucidate their lipid metabolism and immune features, as dysregulation of immune regulatory molecules or immune function is also considered a contributing factor to nephritis onset and progression (38).…”

Section: Discussionmentioning

confidence: 99%

Causal association of plasma circulating metabolites with nephritis: a Mendelian randomization study

Shao,

Yao,

Weng

et al. 2024

Front. Nutr.

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BackgroundNephritis is a pivotal catalyst in chronic kidney disease (CKD) progression. Although epidemiological studies have explored the impact of plasma circulating metabolites and drugs on nephritis, few have harnessed genetic methodologies to establish causal relationships.MethodsThrough Mendelian randomization (MR) in two substantial cohorts, spanning large sample sizes, we evaluated over 100 plasma circulating metabolites and 263 drugs to discern their causal effects on nephritis risk. The primary analytical tool was the inverse variance weighted (IVW) analysis. Our bioinformatic scrutiny of GSE115857 (IgA nephropathy, 86 samples) and GSE72326 (lupus nephritis, 238 samples) unveiled anomalies in lipid metabolism and immunological characteristics in nephritis. Thorough sensitivity analyses (MR-Egger, MR-PRESSO, leave-one-out analysis) were undertaken to verify the instrumental variables’ (IVs) assumptions.ResultsUnique lipoprotein-related molecules established causal links with diverse nephritis subtypes. Notably, docosahexaenoic acid (DHA) emerged as a protective factor for acute tubulointerstitial nephritis (ATIN) (OR1 = 0.84, [95% CI 0.78–0.90], p1 = 0.013; OR2 = 0.89, [95% CI 0.82–0.97], p2 = 0.007). Conversely, multivitamin supplementation minus minerals notably increased the risk of ATIN (OR = 31.25, [95% CI 9.23–105.85], p = 0.004). Reduced α-linolenic acid (ALA) levels due to lipid-lowering drugs were linked to both ATIN (OR = 4.88, [95% CI 3.52–6.77], p < 0.001) and tubulointerstitial nephritis (TIN) (OR = 7.52, [95% CI 2.78–20.30], p = 0.042). While the non-renal drug indivina showed promise for TIN treatment, the use of digoxin, hydroxocobalamin, and liothyronine elevated the risk of chronic tubulointerstitial nephritis (CTIN). Transcriptome analysis affirmed that anomalous lipid metabolism and immune infiltration are characteristic of IgA nephropathy and lupus nephritis. The robustness of these causal links was reinforced by sensitivity analyses and leave-one-out tests, indicating no signs of pleiotropy.ConclusionDyslipidemia significantly contributes to nephritis development. Strategies aimed at reducing plasma low-density lipoprotein levels or ALA supplementation may enhance the efficacy of existing lipid-lowering drug regimens for nephritis treatment. Renal functional status should also be judiciously considered with regard to the use of nonrenal medications.

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Section: Discussionmentioning

confidence: 99%

Causal association of plasma circulating metabolites with nephritis: a Mendelian randomization study

Shao,

Yao,

Weng

et al. 2024

Front. Nutr.

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Cellular dynamics in pig-to-human kidney xenotransplantation

Pan,

Zhang,

Zheng

et al. 2024

Med

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Multiomic analysis of human kidney disease identifies a tractable inflammatory, pro-fibrotic tubular cell phenotype

Conway,

Reck,

Baird

et al. 2024

Preprint

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Maladaptive proximal tubular cells have been implicated in failure of repair following renal injury in rodent models, however whether this translates to human kidney disease is unknown. Hence, we integrated snRNA-ATAC-seq with single-cell molecular imaging to generate a multiomic atlas of human kidney disease. In injured kidneys, a subset of tubular epithelial cells acquired an inflammatory phenotype, enriched with pro-fibrotic and senescence markers, analogous to maladaptive cells in mice. Cell neighborhood analysis positioned the inflammatory phenotype adjacent to leucocytes and myofibroblasts and ligand-receptor analysis highlighted paracrine signaling from inflammatory tubular cells to mediate leucocyte recruitment and myofibroblast activation. Loss of an HNF4α-driven gene regulatory network and activation of NF-κβ and AP-1 transcription factors epigenetically imprinted the inflammatory phenotype. Targeting these inflammatory tubular cells by administration of an AP-1 inhibitor or a senolytic agent ameliorated inflammation, expression of senescence-associated transcripts and fibrosis in murine models of kidney injury suggesting these as therapies for human kidney disease.

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Analysis of the human kidney transcriptome and plasma proteome identifies markers of proximal tubule maladaptation to injury

Cited by 3 publications

References 61 publications

Causal association of plasma circulating metabolites with nephritis: a Mendelian randomization study

Causal association of plasma circulating metabolites with nephritis: a Mendelian randomization study

Cellular dynamics in pig-to-human kidney xenotransplantation

Multiomic analysis of human kidney disease identifies a tractable inflammatory, pro-fibrotic tubular cell phenotype

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