Abstract
Diabetic kidney disease is the leading cause of impaired kidney function, albuminuria, and renal replacement therapy (dialysis or transplantation), thus placing a large burden on health-care systems. This urgent event requires us to reveal the molecular mechanism of this disease to develop more efficacious treatment. Herein, we reported single-cell RNA sequencing analyses in kidneys of db/db mouse, an animal model for type 2 diabetes and diabetic kidney disease. We first analyzed the hub genes expressed differentially in the single cell resolution transcriptome map of the kidneys. Then we figured out the communication among the renal and immune cells in the kidneys. Data from this report may provide novel information for better understanding the cell-specific targets involved in the aetiologia of type 2 diabetic kidney disease and for cell communication and signaling between renal cells and immune cells of this complex disease.
Similar content being viewed by others
Data availability
The datasets and computer code produced in this study are available in the following databases: Our scRNA-Seq data: Sequence Read Archive PRJNA749372 (https://www.ncbi.nlm.nih.gov/sra/PRJNA749372). In order to provide scRNA profiles from this study, we have constructed an interactive shiny-app as a web tool for your visit (http://biomamba.com:34038/DKD.data.set/). Referenced scRNA-Seq data: Gene Expression Omnibus GSE107585 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE107585). Other original contributions are included in this article, including tables, figures, and supplementary material.
Abbreviations
- AGEs:
-
Advanced glycation end products
- ALH:
-
Ascending loop of Henle
- BCAA:
-
Branched-chain amino acids
- CD-IC:
-
Collecting duct intercalated cell
- CD-PC:
-
Collecting duct principal cell
- CR:
-
Creatinine
- DCT:
-
Distal convoluted tubule
- DEGs:
-
Differentially expressed genes
- DLH:
-
Descending loop of Hence
- DKD:
-
Diabetic kidney disease
- DM:
-
Diabetes mellitus
- EERA:
-
Erythropoietin receptor
- EnC:
-
Endothelial cell
- ESKF:
-
End-stage kidney failure
- GO:
-
Gene ontology
- IDF:
-
International Diabetes Federation
- KAP:
-
Kidney androgen-regulated protein
- KEGG:
-
Kyoto encyclopedia of genes and genomes
- Mac:
-
Macrophage
- mtRNA:
-
Mitochondrial RNA
- OPN:
-
Osteopontin
- PCT:
-
Proximal convoluted tubule
- PTCs:
-
Proximal epithelial tubular cells
- RAAS:
-
Renin–angiotensin–aldosterone system
- RSCEP:
-
Renal stromal cells except PTCs
- scRNA-seq:
-
Single-cell RNA sequencing
- SNN:
-
Shared nearest neighbor
- STZ:
-
Streptozotocin
- T1D:
-
Type 1 diabetes
- T2D:
-
Type 2 diabetes
- tSNE:
-
T-distributed stochastic neighbor embedding
- UA:
-
Urinary albuminuria
- UAER:
-
Urinary albumin excretion rate
- UMAP:
-
Uniform manifold approximation and projection
- UMI:
-
Unique molecular identifiers
References
Anders HJ, Huber TB, Isermann B, Schiffer M (2018) CKD in diabetes: diabetic kidney disease versus nondiabetic kidney disease. Nat Rev Nephrol 14(6):361–377
Bai M, Chen H, Ding D, Song R, Lin J, Zhang Y, Guo Y, Chen S, Ding G, Zhang Y et al (2019) MicroRNA-214 promotes chronic kidney disease by disrupting mitochondrial oxidative phosphorylation. Kidney Int 95:1389–1404
Beale EG, Harvey BJ, Forest C (2007) PCK1 and PCK2 as candidate diabetes and obesity genes. Cell Biochem Biophys 48:89–95
Bondeva T, Wolf G (2015) Role of neuropilin-1 in diabetic nephropathy. J Clin Med 4:1293–1311
Boyd-Shiwarski CR, Shiwarski DJ, Roy A, Namboodiri HN, Nkashama LJ, Xie J, McClain KL, Marciszyn A, Kleyman TR, Tan RJ et al (2017) Potassium-regulated distal tubule WNK bodies are kidney-specific WNK1 dependent. Mol Biol Cell 229:499–509
Crambert G, Geering K (2003) FXYD proteins: new tissue-specific regulators of the ubiquitous Na,K-ATPase. Sci Signal 2003(166):re1–re1. https://doi.org/10.1126/scisignal.1662003re1
Crisi GM, Marconi SA, Rockwell GF, Braden GL, Campfield TJ (2009) Immuno-localization of CD44 and osteopontin in developing human kidney. Pediatr Res 65:79–84
de Quixano BB, Villena JA, Aranda M, Brils G, Cuevas A, Hespel T, Lekuona H, Súarez C, Tornavaca O, Meseguer A (2017) Kidney androgen-regulated protein (KAP) transgenic mice are protected against high-fat diet induced metabolic syndrome. Sci Rep 7:16102
Doshi SM, Friedman AN (2017) Diagnosis and management of Type 2 diabetic kidney disease. Clin J Am Soc Nephrol 12:1366–1373
Du Y, Yang YT, Tang G, Jia JS, Zhu N, Yuan WJ (2020) Butyrate alleviates diabetic kidney disease by mediating the miR-7a-5p/P311/TGF-β1 pathway. FASEB J 34:10462–10475
Fu J, Akat KM, Sun Z, Zhang W, Schlondorff D, Liu Z, Tuschl T, Lee K, He JC (2019a) Single-Cell RNA profiling of glomerular cells shows dynamic changes in experimental diabetic kidney disease. J Am Soc Nephrol 30:533–545
Fu J, Lee K, Chuang PY, Liu Z, He JC (2019b) Glomerular endothelial cell injury and cross talk in diabetic kidney disease. Am J Physiol Renal Physiol 308:F287-297
Fuchs TC, Hewitt P (2011) Biomarkers for drug-induced renal damage and nephrotoxicity-an overview for applied toxicology. AAPS J 13:615–631
Furman BL (2015) Streptozotocin‐induced diabetic models in mice and rats. Curr Protoc Pharmacol. https://doi.org/10.1002/0471141755.ph0547s70
Jiang NM, Cowan M, Moonah SN, Petri WA Jr (2018) (2018) The impact of systemic inflammation on neurodevelopment. Trends Mol Med 24(9):794–804
Kaleta B (2019) The role of osteopontin in kidney diseases. Inflamm Res 68:93–102
Kim Y, Park CW (2019) Mechanisms of adiponectin action: implication of adiponectin receptor agonism in diabetic kidney disease. Int J Mol Sci 20:1782
Li Y, Huang J, He S, Lu Z, Zhang J, Li X, Yang Z, Hoffman RM, Wu Q (2020) APELA/ELA32 Reduces iodixanol-induced apoptosis, inflammatory response and mitochondrial and dna damage in renal tubular epithelial cells. Anticancer Res 40:635–643
Ma T, Lopez-Aguiar AG, Li A, Lu Y, Sekula D, Nattie EE, Freemantle S, Dmitrovsky E (2014) Mice lacking G0S2 are lean and cold-tolerant. Cancer Biol Ther 15:643–650
Macosko EZ, Basu A, Satija R, Nemesh J, Shekhar K, Goldman M, Tirosh I, Bialas AR, Kamitaki N, Martersteck EM et al (2015) Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets. Cell 161:1202–1214
Mantovani A, Dinarello CA, Molgora M, Garlanda C (2019) Interleukin-1 and related cytokines in the regulation of inflammation and immunity. Immunity 50(4):778–795
Matsunaga N, Ikeda E, Kakimoto K, Watanabe M, Shindo N, Tsuruta A, Ikeyama H, Hamamura K, Higashi K, Yamashita T et al (2016) Inhibition of G0/G1 switch 2 ameliorates renal inflammation in chronic kidney disease. EBioMedicine 13:262–273
Mihai S, Codrici E, Popescu ID, Enciu AM, Rusu E, Zilisteanu D, Necula LG, Anton G, Tanase C (2019) Inflammation-related patterns in the clinical staging and severity assessment of chronic kidney disease. Dis Markers 2019:1814304
Northrup TE, Irwin D, Malt RA (1977) Ribosomal proteins of mouse kidney: normal status and during compensatory renal hypertrophy. Mol Cell Biochem 17:25–30
Park J, Shrestha R, Qiu C, Kondo A, Huang S, Werth M, Li M, Barasch J, Suszták K (2018) Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease. Science 360:758–763
Patouraux S, Rousseau D, Bonnafous S, Lebeaupin C, Luci C, Canivet CM, Schneck AS, Bertola A, Saint-Paul MC, Iannelli A et al (2017) CD44 is a key player in non-alcoholic steatohepatitis. J Hepatol 67:328–338
Piaszyk-Borychowska A, Széles L, Csermely A, Chiang HC, Wesoły J, Lee CK, Nagy L, Bluyssen HAR (2019) Signal integration of IFN-I and IFN-II With TLR4 involves sequential recruitment of STAT1-complexes and NFκB to enhance pro-inflammatory transcription. Front Immunol 10:1253
Seo W, Shimizu K, Kojo S, Okeke A, Kohwi-Shigematsu T, Fujii SI, Taniuchi I (2020) Runx-mediated regulation of CCL5 via antagonizing two enhancers influences immune cell function and anti-tumor immunity. Nat Commun 11(1):1562
Sharma K, McCue P, Dunn SR (2003) Diabetic kidney disease in the db/db mouse. Am J Physiol Renal Physiol 284:F1138-1144
Sheng J, Li H, Dai Q, Lu C, Xu M, Zhang J, Feng J (2019) DUSP1 recuses diabetic nephropathy via repressing JNK-Mff-mitochondrial fission pathways. J Cell Physiol 234:3043–3057
Shirakawa K, Sano M (2020) Sodium-glucose Co-transporter 2 inhibitors correct metabolic maladaptation of proximal tubular epithelial cells in high-glucose conditions. Int J Mol Sci 21:7676
Stables MJ, Shah S, Camon EB, Lovering RC, Newson J, Bystrom J, Farrow S, Gilroy DW (2011) Transcriptomic analyses of murine resolution-phase macrophages. Blood 118:e192-208
Su H, Na N, Zhang X, Zhao Y (2017) The biological function and significance of CD74 in immune diseases. Inflamm Res 66:209–216
Sweadner KJ, Arystarkhova E, Donnet C, Wetzel RK (2003) FXYD proteins as regulators of the Na, K-ATPase in the kidney. Ann N Y Acad Sci 986:382–387
Tang F, Barbacioru C, Wang Y, Nordman E, Lee C, Xu N, Wang X, Bodeau J, Tuch BB, Siddiqui A et al (2009) mRNA-Seq whole-transcriptome analysis of a single cell. Nat Methods 6:377–382
Thomas MC, Brownlee M, Susztak K, Sharma K, Jandeleit-Dahm KAM, Zoungas S, Rossing P, Groop PH, Cooper ME (2015) Diabetic kidney disease. Nat Rev Dis Primers. https://doi.org/10.1038/nrdp.2015.18
Thomas MC, Cooper ME, Zimmet P (2016) Changing epidemiology of type 2 diabetes mellitus and associated chronic kidney disease. Nat Rev Nephrol 12:73–81
Valiño-Rivas L, Baeza-Bermejillo C, Gonzalez-Lafuente L, Sanz AB, Ortiz A, Sanchez-Niño MD (2015) CD74 in kidney disease. Front Immunol 6:483
Wang Y, Lu YH, Tang C, Xue M, Li XY, Chang YP, Cheng Y, Li T, Yu XC, Sun B et al (2019) Calcium dobesilate restores autophagy by inhibiting the VEGF/PI3K/AKT/mTOR signaling pathway. Front Pharmacol 10:886
Wilson PC, Wu H, Kirita Y, Uchimura K, Ledru N, Rennke HG, Welling PA, Waikar SS, Humphreys BD (2019) The single-cell transcriptomic landscape of early human diabetic nephropathy. Proc Natl Acad Sci USA 116(39):19619–19625
Xu F, Zhou H, Wu M, Zhang H, Zhang Y, Zhao Q, Brown R, Gong DW, Miao L (2020) Fc-elabela fusion protein attenuates lipopolysaccharide-induced kidney injury in mice. Biosci Rep 40:BSR20192397
Yang XH, Pan Y, Zhan XL, Zhang BL, Guo LL, Jin HM (2016) Epigallocatechin-3-gallate attenuates renal damage by suppressing oxidative stress in diabetic db/db mice. Oxid Med Cell Longev 2016:2968462
Zhang Y, Li W, Zhou Y (2020) Identification of hub genes in diabetic kidney disease via multiple-microarray analysis. Ann Transl Med 8:997
Zheng GX, Terry JM, Belgrader P, Ryvkin P, Bent ZW, Wilson R, Ziraldo SB, Wheeler TD, McDermott GP, Zhu J et al (2017) Massively parallel digital transcriptional profiling of single cells. Nat Commun 8:14049
Acknowledgements
The authors wish to thank Dr. Katalin Susztak for her positive agreement and valuable discussion.
Funding
This study was supported by the start grants from China Pharmaceutical University (CPU20180815 HFG), the Cooperation Research Project (CPU20200228 HFG).
Author information
Authors and Affiliations
Contributions
Conceived and designed the experiments: Harvest F. Gu; Data acquisition and analysis: Chenhua Wu, Yingjun Tao, Nan Li, Jingjin Fei; Laboratory management: Yurong Wang; Data interpretation: Jie Wu, and Harvest F. Gu; Manuscript preparation and revision: Chenhua Wu and Harvest F. Gu; All authors agreed and approved the final version of manuscript.
Corresponding authors
Ethics declarations
Conflict of interests
The authors declare no competing interests.
Consent for publication
The authors of the manuscript have read and agreed to the consent for publication.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Wu, C., Tao, Y., Li, N. et al. Prediction of cellular targets in diabetic kidney diseases with single-cell transcriptomic analysis of db/db mouse kidneys. J. Cell Commun. Signal. 17, 169–188 (2023). https://doi.org/10.1007/s12079-022-00685-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12079-022-00685-z