Mapping the single-cell transcriptomic response of murine diabetic kidney disease to therapies

Wu, Haojia; Villalobos, Romer Gonzalez; Yao, Xiang; Reilly, Dermot F.; Chen, Tao; Rankin, Matthew M.; Myshkin, Eugene; Breyer, Matthew D.; Humphreys, Benjamin D.

doi:10.1016/j.cmet.2022.05.010

Cited by 115 publications

(85 citation statements)

References 62 publications

(70 reference statements)

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“…We used a k-nearest neighbor graph (k-NNG)-based Leiden clustering (Traag et al, 2019) to detect the distinct cell populations and Uniform Manifold Approximation and Projection (UMAP) (Becht et al, 2019) for data embedding and two-dimensional reduction. UMAP visualization of the core GBmap ( Figure 1b ) was generated using the plot1cell package (Wu et al, 2022). Total count normalization was done by initially dividing each count by the total count per cell and multiplying by 10,000, followed by log transformation using a natural log ( X +1).…”

Section: Methodsmentioning

confidence: 99%

Harmonized single-cell landscape, intercellular crosstalk and tumor architecture of glioblastoma

Ruiz-Moreno

Salas

Samuelsson

et al. 2022

Preprint

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Glioblastoma, isocitrate dehydrogenase (IDH)-wildtype (hereafter, GB), is an aggressive brain malignancy associated with a dismal prognosis and poor quality of life. Single-cell RNA sequencing has helped to grasp the complexity of the cell states and dynamic changes in GB. Large-scale data integration can help to uncover unexplored tumor pathobiology. Here, we resolved the composition of the tumor milieu and created a cellular map of GB ("GBmap"), a curated resource that harmonizes 26 datasets gathering 240 patients and spanning over 1.1 million cells. We showcase the applications of our resource for reference mapping, transfer learning, and biological discoveries. Our results uncover the sources of pro-angiogenic signaling and the multifaceted role of mesenchymal-like cancer cells. Reconstructing the tumor architecture using spatially resolved transcriptomics unveiled a high level of well-structured neoplastic niches. The GBmap represents a framework that allows the streamlined integration and interpretation of new data and provides a platform for exploratory analysis, hypothesis generation and testing.

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Section: Methodsmentioning

confidence: 99%

Harmonized single-cell landscape, intercellular crosstalk and tumor architecture of glioblastoma

Ruiz-Moreno

Salas

Samuelsson

et al. 2022

Preprint

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“…To validate the observed reversal by SGLT2i of metabolic pathways and genes in tubular segments impacted by T2Di(-), we compared this cohort to the transcriptional data from control and SGLT2i-treated ReninAAV db/db mice after uninephrectomy(29). The suppression of glycolysis, gluconeogenesis, TCA cycle, β-oxidation and glutathione conjugation with SGLT2 inhibition observed in the human PT were replicated in the murine kidney transcriptomic data ( Figure 6 , Supplemental Table 4 ).…”

Section: Resultsmentioning

confidence: 99%

“…To validate our findings in the human data, we used RNA-sequencing data from the kidney tissue of recently published mouse models. In brief, female db/db mice BKS.Cg-Dock7m +/+ Leprdb/J from Jackson, BKS background, Lot 642) underwent left nephrectomy at 5 weeks of age and, at 12 weeks, infected with renin expressing adeno-associated virus (ReninAAV, 109 genomic copies), which accelerates disease progression (29). We compared ReninAAV Uninephrectomy db/db mice who received 2 weeks of SGLT2 inhibitor treatment with untreated ReninAAV Uninephrectomy db/db mice.…”

Section: Murine Modelsmentioning

confidence: 99%

SGLT2 inhibition mitigates perturbations in nephron segment-specific metabolic transcripts and mTOR pathway activity in kidneys of young persons with type 2 diabetes

Schaub

Alakwaa

McCown

et al. 2022

Preprint

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The molecular mechanisms of SGLT2 inhibitors (SGLT2i) remain incompletely understood. Single-cell RNA sequencing and morphometrics data were collected from research kidney biopsies donated by participants with youth onset type 2 diabetes (T2D), aged 12-21 years of age, and healthy controls (HC) to study the effects of SGLT2i on kidney transcriptomics. Participants with T2D were more obese, had higher glomerular filtration rate, mesangial and glomerular volumes than HC. There were no clinically significant differences between participants prescribed SGLT2i (T2Di(+), n=10) and other T2D (T2Di(-), n=6). Transcriptional profiles showed SGLT2 expression exclusively in the proximal tubular (PT) cluster. Transcriptional alterations in T2Di(+) compared to T2Di(-) were seen across most nephron segments, most prominently in the distal nephron. SGLT2i treatment was associated with suppression of genes in the glycolysis, gluconeogenesis, tricarboxylic acid cycle pathways in PT, but enhanced expression in thick ascending limb. The energy sensitive mTOR signaling pathway transcripts were suppressed towards HC level in all nephron segments in T2Di(+). These transcriptional changes were confirmed in a diabetes mouse model treated with SGLT2i. Therefore, the beneficial effects of SGLT2i treatment to the kidneys might be from mitigating diabetes-induced metabolic perturbations via suppression of mTORC1 signaling across nephron segments, including those not expressing SGLT2.

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“…Additional, scRNA-seq was used to analyze the response of DN mouse models to five common treatment regimens and found that different drugs had significantly different effects on cell types, even with combination therapy. ( Wu et al, 2022 ). The existence of computational cell trajectory analysis methods allows to simulate the process of the kidney from a normal state to the onset of lesions, thus avoiding experimental errors.…”

Section: The Role Of Proteomics and Scrna-seq In Dn Researchmentioning

confidence: 99%

Early renal structural changes and potential biomarkers in diabetic nephropathy

2022

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Diabetic nephropathy is one of the most serious microvascular complications of diabetes mellitus, with increasing prevalence and mortality. Currently, renal function is assessed clinically using albumin excretion rate and glomerular filtration rate. But before the appearance of micro-albumin, the glomerular structure has been severely damaged. Glomerular filtration rate based on serum creatinine is a certain underestimate of renal status. Early diagnosis of diabetic nephropathy has an important role in improving kidney function and delaying disease progression with drugs. There is an urgent need for biomarkers that can characterize the structural changes associated with the kidney. In this review, we focus on the early glomerular and tubular structural alterations, with a detailed description of the glomerular injury markers SMAD1 and Podocalyxin, and the tubular injury markers NGAL, Netrin-1, and L-FABP in the context of diabetic nephropathy. We have summarized the currently studied protein markers and performed bioprocess analysis. Also, a brief review of proteomic and scRNA-seq method in the search of diabetic nephropathy.

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Mapping the single-cell transcriptomic response of murine diabetic kidney disease to therapies

Cited by 115 publications

References 62 publications

Harmonized single-cell landscape, intercellular crosstalk and tumor architecture of glioblastoma

Harmonized single-cell landscape, intercellular crosstalk and tumor architecture of glioblastoma

SGLT2 inhibition mitigates perturbations in nephron segment-specific metabolic transcripts and mTOR pathway activity in kidneys of young persons with type 2 diabetes

Early renal structural changes and potential biomarkers in diabetic nephropathy

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