Single-Cell Transcriptional Landscape Reveals the Regulatory Network and Its Heterogeneity of Renal Mitochondrial Damages in Diabetic Kidney Disease
Abstract
:1. Introduction
2. Results
2.1. Pathological Features and Reactive Oxygen Species
2.2. Renal scRNA-Seq Data Preparation, Clustering, and Quality Control
2.3. Mitochondrial Encoding mRNA Content
2.4. Mitochondria-Associated Nuclear Genes Were Involved in the Process of DKD
2.5. SLC Superfamily Intervened in the Process of DKD by Affecting Cellular Metabolism and Oxidative Stress through Substance Transport Function
2.6. Differential Expression of ESDEGs Was Controlled by a Hierarchical Receptor-TF-TG Regulatory Network Formed in Cell Communication
3. Discussion
4. Methods and Materials
4.1. Animal Management
4.2. Reactive Oxygen Species, Hematoxylin-Eosin, and Periodic Acid-Schiff Stain
4.3. Transmission Electron Microscopy
4.4. ScRNA-Seq Data Preprocessing, Dimension Reduction, Clustering, Cell Annotation and Quality Control
4.5. Gene Set Scoring and Enrichment Analysis
4.6. Cell Communication Prediction
4.7. Transcription Factor Prediction
4.8. Bulk RNA-Seq Was Deconvolved by Cibersort Using the scRNA-Seq Data
4.9. scRNA-Seq Labels Transformation
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Statistics
Abbreviations
ALH | Ascending loop of Henle |
ARB | angiotensin receptor blockers |
AUC | area under the curve |
BG | blood glucose |
CD-IC | Collecting duct intercalated cell |
CD-PC | collecting duct principal cell |
CKD | chronic kidney disease |
CPU | China Pharmaceutical University |
DA | different analysis |
DCCP | different cell communication pathway |
DCP | DKD-conventional pathways |
DCT | Distal convoluted tubule |
DDC | DKD-dominant Cluster |
DEG | differently expressed gene |
DKD | Diabetic kidney disease |
DLH | descending loop of Henle |
DM | diabetes mellitus |
DRSC | distal renal stromal cells |
EMT | epithelial-mesenchymal transition |
EnC | endothelial cell |
ESDEG | exclusive significant difference gene |
FDR | false discovery rate |
GO | Gene Ontology |
GSVA | gene set variation analysis |
HDC | health-dominant cluster |
HE | Hematoxylin-Eosin |
HKC | Huangkui capsule |
kcdf | Kernel estimation of the cumulative density function |
KEGG | Kyoto Encyclopedia of Genes and Genomes |
KW | Kimmelstiel–Wilson |
Mac | macrophage |
MANG | mitochondria-associated nuclear gene |
NCBI | National Center for Biotechnology Information |
NES | normalized enrichment score |
pANN | proportion of artificial nearest neighbors |
PAS | Periodic Acid-Schiff stain |
PC | principal component |
PMEM | percentages of mitochondrial encoding |
ROS | reactive oxygen species |
S1 | segment 1 |
scRNA-Seq | single-cell RNA sequencing |
snRNA-Seq | single nuclear RNA-Seq (snRNA-Seq) |
SGLT2i | Sodium-glucose cotransporter-2 inhibitor |
SLC | solute carrier |
ssGSEA | single sample gene set enrichment analysis |
TF | transcription factor |
TG | target gene |
TPM | transcripts per million |
TSS | transcriptional start site |
UACR | urinary albumin-to-creatinine ratio |
UMAP | uniform manifold approximation and projection |
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Cell Type | DEP | Dims of PCA | Resolution |
---|---|---|---|
S1 | 138 | 20 | 0.1 |
S2 | 127 | 19 | 0.08 |
S3 | 142 | 20 | 0.1 |
DLH | 67 | 3 | 0.15 |
ALH | 119 | 16 | 0.1 |
DCT | 129 | 15 | 0.1 |
CD-PC | 125 | 8 | 0.1 |
CD-IC | 104 | 9 | 0.2 |
EnC | 44 | 3 | 0.15 |
T Cell | 86 | 10 | 0.1 |
B cell | 32 | 2 | 0.1 |
Mac | 76 | 3 | 0.1 |
DC | 10 | NA | NA |
Gene | As Marker in | Substrate |
---|---|---|
Slc12a1 | ALH | sodium-potassium-chloride |
Slc16a7 | DCT | lactate, pyruvate, ketone bodies |
Slc26a4 | CD-IC | sulfate |
Slc43a2 | CD-IC | L-isomers of neutral amino acids, including leucine, phenylalanine, valine and methionine |
Slc4a9 | CD-IC | anion |
Slc8a1 | CD-PC | Ca2+ |
Slc12a3 | DCT | Sodium, chloride |
Slc27a2 | PTC | free long-chain fatty acids |
Slc34a1 | PTC | sodium-phosphate |
Slc13a3 | S3 | succinate and other Krebs cycle intermediates |
Slc17a1 | S1, S3 | - |
Slc17a3 | S3 | intracellular urate and organic anions |
Slc22a30 | S3 | - |
Slc22a1 | S1, S3 | organic cation |
Slc22a12 | S3 | urate |
Slc22a8 | S1, S3 | organic anions |
Slc23a1 | S1, S3 | vitamin C |
Slc2a2 | S1, S3 | glucose |
Slc6a20b | S1, S3 | - |
Slc37a4 | S1, S3 | glucose-6-phosphate |
Slc3a1 | S1, S3 | neutral and basic amino acids |
Slc47a1 | S1, S3 | - |
Slc4a4 | S1, S3 | bicarbonate |
Slc6a19 | S1 | neutral amino acids |
Slc5a12 | S1 | lactate |
Slc5a2 | S1 | sodium, glucose |
Slc7a7 | S1 | cationic amino acid, neutral amino acids |
Slc7a8 | S1 | - |
Slc22a6 | S3 | sodium, organic anions |
Slc5a10 | S3 | sodium, glucose, ascorbate, choline, iodide, lipoate, monocaroboxylates, pantothenate |
Slc6a18 | S3 | sodium, neurotransmitters, amino acids, and osmolytes (eg., betaine, taurine, and creatine). |
Slc5a8 | S3 | lactate, monocarboxylates, short-chain fatty acids, sodium |
Slc43a3 | EnC | - |
Slc9a3r2 | EnC | sodium, hydrogen |
Gene | As DEG in | Substrate |
---|---|---|
Slc25a25 | DLH, Mac | ATP, Ca2+ |
Slc25a5 | DLH, CD-PC, EnC, B cell | adenine nucleotide |
Slc25a51 | DLH | NAD |
Slc25a16 | DLH, B cell, EnC | nucleotide |
Slc25a3 | DLH, CD-PC, EnC | phosphate |
Slc25a15 | B cell, EnC | L-arginine, L-lysine, L-ornithine |
Slc25a4 | B cell, CD-PC | ATP/ADP antiporter |
Slc25a42 | DLH | adenylic acid, coenzyme A |
Slc25a30 | CD-PC | C4-dicarboxylate, sulfur compound |
Slc25a39 | DLH, B cell, CD-PC, Mac | glutathione |
Slc25a10 | DLH, B cell, Mac | dicarboxylic acid, malate, oxaloacetate, phosphate ion, succinate, sulfate |
Gene | As DEG in | Substrate |
---|---|---|
Slc27a2 | B cell, EnC, Mac | long-chain fatty acids |
Slc6a18 | DLH | Sodium, neurotransmitters, amino acids, osmolytes (e.g., betaine, taurine, and creatine). |
Slc34a1 | DLH, CD-PC, EnC, B cell, Mac | sodium-phosphate |
Slc4a4 | DLH, B cell. EnC, Mac | bicarbonate |
Slc7a13 | DLH | L-cystine, L-glutamate, aspartate |
Slc23a1 | DLH, B cell | vitamin C |
Slc3a1 | DLH, EnC, B cell | neutral and basic amino acids |
Slc7a12 | DLH | amino acid |
Slc47a1 | DLH, EnC, B cell | L-arginine |
Slc17a1 | DLH, EnC, B cell, Mac | sialic acid |
Slc5a8 | DLH, EnC, Mac | lactate, monocarboxylates, short-chain fatty acids, sodium |
Slc13a1 | DLH, EnC, B cell. Mac | sodium-sulfate symporter |
Slc9a3r1 | DLH | dopamine receptor, phosphatase |
Slc16a9 | DLH, EnC, Mac | carnitine, monocarboxylic acid, creatine |
Slc12a3 | DLH, CD-PC, | sodium, chloride |
Slc22a12 | DLH, EnC, B cell, Mac | urate |
Slc6a13 | DLH | taurine, amino acid, creatine, gamma-aminobutyric acid, monocarboxylic acid, neurotransmitter |
Slc5a10 | DLH, EnC, Mac | sodium, glucose, ascorbate, choline, iodide, lipoate, pantothenate |
Slc22a1 | DLH, EnC, B cell | organic cation |
Slc22a18 | DLH, EnC | organic anion, ubiquitin protein ligase |
Slc10a2 | DLH | bile acid-sodium |
Slc5a2 | DLH, B cell, Mac | Sodium, glucose |
Slco3a1 | DLH, B cell | Oligopeptide, sodium-independent organic anion, prostaglandin |
Slc17a3 | DLH | intracellular urate and organic anions |
Slc5a12 | DLH, B cell | lactate |
Slc2a5 | DLH, Mac | fructose, glucose |
Slc22a13 | DLH | nicotinate, urate |
Slco4c1 | DLH | sodium-independent organic anion |
Slc2a2 | DLH, B cell, Mac | glucose |
Slc6a20b | DLH, B cell | L-proline |
Slc15a2 | DLH | dipeptide, oligopeptide |
Slc29a3 | DLH, Mac | nucleoside |
Slc22a6 | DLH, EnC, B cell, Mac | sodium, organic anions |
Slc22a30 | DLH, B cell | short-chain fatty acid |
Slc38a3 | DLH | L-glutamine, L-histidine |
Slc16a2 | DLH, EnC B cell | monocarboxylic acid, thyroid hormone |
Slc16a4 | DLH, Mac | monocarboxylic acid |
Slc51b | DLH | bile acid |
Slc23a3 | DLH | vitamin C, sodium |
Slco1a6 | DLH, B cell, Mac | bile acid, sodium-independent organic anion |
Slc38a2 | DLH | L-glutamine, L-serine |
Slco4a1 | DLH | sodium-independent organic anion, thyroid hormone |
Slc22a23 | DLH | NA |
Slc12a2 | DLH | K+, Hsp90, ammonium, sodium-potassium-chloride |
Slc4a7 | B cell | sodium-bicarbonate symporter |
Slc30a9 | B cell, Mac | monatomic cation, nuclear receptor |
Slc6a19 | B cell, Mac | neutral amino acids |
Slc37a4 | EnC, B cell, Mac | glucose-6-phosphate |
Slc22a8 | B cell, Mac | organic anions |
Slc4a7 | B cell | sodium-bicarbonate symporter |
Slc39a1 | B cell | Zn2+ |
Slc13a3 | EnC, B cell, Mac | succinate and other Krebs cycle intermediates |
Slc26a2 | B cell | bicarbonate, chloride, oxalate, sulfate |
Slc12a7 | B cell | ammonium, potassium-chloride symporter |
Slc8a1 | CD-PC | Ca2+ |
Slc25a30 | CD-PC | C4-dicarboxylate, sulfur compound |
Slc2a4 | CD-PC | glucose, insulin-responsive glucose-proton symporter |
Slc6a6 | CD-PC | beta-alanine, taurine |
Slc2a1 | CD-PC | glucose, dehydroascorbic acid, long-chain fatty acid |
Slc44a1 | CD-PC, EnC | choline |
Slc35a1 | EnC | CMP-N-acetylneuraminate, pyrimidine nucleotide-sugar |
Slc39a3 | EnC | Zn2+ |
Slc35a4 | Mac | pyrimidine nucleotide-sugar |
Slc7a8 | Mac | glycine |
Slc35f5 | Mac | NA |
Slc16a1 | Mac | Lactate, carboxylic acid, succinate |
Slc22a5 | Mac | carnitine, nucleotide |
Slc9a3 | Mac | Na+-H+, K+-H+ |
Slc20a2 | Mac | inorganic phosphate |
Slc1a1 | Mac | aspartate, glutamate, chloride, cysteine |
Cluster | Role in Communication | Pathway | DEG |
---|---|---|---|
DLH_HDC | Source | WNT, COLLAGEN, AGRN, APP, L1CAM | Wnt7b, Col4a3, Col4a4, Col4a5, Agrn, App, L1cam |
DLH_DDC | Source | EGF, COLLAGEN, AGRN, APP | Egf, Fgf1, Col4a3, Col4a4, Col4a5, Agrn, App |
CD-PC_HDC | Source | KIT, COLLAGEN, APP, JAM, F11r | Kitl, Col4a4, App |
CD-PC_DDC | Source | KIT, COLLAGEN, APP, JAM | Kitl, Col4a4, App, F11r |
EnC_HDC | Source | VEGF, VISFATIN, COLLAGEN | Vegfa, Nampt, Col4a4 |
EnC_DDC | Source | TGFb | Tgfb1 |
B cell_HDC | Source | MHC-II | H2-Ab1, H2-Ob |
B cell_DDC | Source | TGFb, MHC-II, SELL | Tgfb1, H2-Ab1, H2-Ob, Sell |
Mac_HDC | Source | MIF, SPP1, COLLAGEN, JAM | Mif, Spp1, Col4a3, F11r |
Mac_DDC | Source | MIF | Mif |
DLH_HDC | Target | ANGPTL, COLLAGEN, FN1, AGRN, LAMININ | Sdc4, Dag1 |
DLH_DDC | Target | ANGPTL, COLLAGEN, FN1, AGRN, LAMININ | Sdc4, Dag1 |
CD-PC_HDC | Target | ncWNT, JAM | Fzd7, F11r |
CD-PC_DDC | Target | JAM | F11r |
EnC_HDC | Target | NULL | NULL |
EnC_DDC | Target | NULL | NULL |
B cell_HDC | Target | APP | Cd74 |
B cell_DDC | Target | APP | Cd74 |
Mac_HDC | Target | JAM | F11r |
Mac_DDC | Target | NULL | NULL |
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Wu, C.; Song, Y.; Yu, Y.; Xu, Q.; Cui, X.; Wang, Y.; Wu, J.; Gu, H.F. Single-Cell Transcriptional Landscape Reveals the Regulatory Network and Its Heterogeneity of Renal Mitochondrial Damages in Diabetic Kidney Disease. Int. J. Mol. Sci. 2023, 24, 13502. https://doi.org/10.3390/ijms241713502
Wu C, Song Y, Yu Y, Xu Q, Cui X, Wang Y, Wu J, Gu HF. Single-Cell Transcriptional Landscape Reveals the Regulatory Network and Its Heterogeneity of Renal Mitochondrial Damages in Diabetic Kidney Disease. International Journal of Molecular Sciences. 2023; 24(17):13502. https://doi.org/10.3390/ijms241713502
Chicago/Turabian StyleWu, Chenhua, Yuhui Song, Yihong Yu, Qing Xu, Xu Cui, Yurong Wang, Jie Wu, and Harvest F. Gu. 2023. "Single-Cell Transcriptional Landscape Reveals the Regulatory Network and Its Heterogeneity of Renal Mitochondrial Damages in Diabetic Kidney Disease" International Journal of Molecular Sciences 24, no. 17: 13502. https://doi.org/10.3390/ijms241713502
APA StyleWu, C., Song, Y., Yu, Y., Xu, Q., Cui, X., Wang, Y., Wu, J., & Gu, H. F. (2023). Single-Cell Transcriptional Landscape Reveals the Regulatory Network and Its Heterogeneity of Renal Mitochondrial Damages in Diabetic Kidney Disease. International Journal of Molecular Sciences, 24(17), 13502. https://doi.org/10.3390/ijms241713502