2. Academic Validation
  3. Single cell G-protein coupled receptor profiling of Transcription factor 21 expressing activated kidney fibroblasts

Single cell G-protein coupled receptor profiling of Transcription factor 21 expressing activated kidney fibroblasts

  • Br J Pharmacol. 2023 Apr 28. doi: 10.1111/bph.16101.
Harmandeep Kaur 1,  Veera Ganesh Yerra 1,  Sri Nagarjun Batchu 1,  Duc Tin Tran 1,  Md Golam Kabir 1,  Youan Liu 1,  Suzanne L Advani 1,  Phelopater Sedrak 1 2,  Laurette Geldenhuys 3,  Karthik K Tennankore 4,  Penelope Poyah 4,  Ferhan S Siddiqi 4,  Andrew Advani 1
Affiliations

Affiliations

  • 1 Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
  • 2 Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
  • 3 Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
  • 4 Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
PMID: 37115600 DOI: 10.1111/bph.16101
Abstract

Background and purpose: Activated fibroblasts deposit fibrotic matrix in chronic kidney disease (CKD) and G-protein coupled receptors (GPCRs) are the most druggable therapeutic targets. Here, we set out to establish a transcriptional profile that identifies activated kidney fibroblasts and the GPCRs that they express.

Experimental approach: RNA Sequencing and single cell qRT-PCR were performed on mouse kidneys after unilateral ureteral obstruction (UUO). Candidate expression was evaluated in mice with UUO or diabetes or injected with adriamycin or folic acid. Intervention studies were conducted in mice with diabetes or UUO. Correlative histology was performed in human kidney tissue.

Key results: Transcription factor 21 (Tcf21)+ cells that expressed 2 or 3 of Postn, Acta2 and Pdgfra were highly enriched for fibrogenic genes and were defined as activated kidney fibroblasts. Tcf21+ α-smooth muscle actin (α-SMA)+ interstitial cells accumulated in the kidneys of mice with UUO or diabetes or injected with adriamycin or folic acid, whereas Renin angiotensin system blockade attenuated increases in Tcf21 in diabetic mice. Fifty-six GPCRs were upregulated in single Tcf21+ kidney fibroblasts, the most upregulated being Adgra2 and S1PR3. The adenosine receptors, Adora2a/2b were upregulated in Tcf21+ fibroblasts and the Adenosine Receptor Antagonist, caffeine decreased Tcf21 upregulation and kidney fibrosis in UUO mice. TCF21, ADGRA2, S1PR3 and ADORA2A/2B were each detectable in α-SMA+ interstitial cells in human kidneys.

Conclusion and implications: Tcf21 is a marker of kidney fibroblasts that are enriched for fibrogenic genes in CKD. Study of GPCRs expressed by these cells may identify new opportunities for CKD therapeutics.

Keywords

Adenosine receptor; Fibroblast; Fibrosis; GPCR; Kidney; Tcf21.

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