A2A receptor-induced overexpression of pannexin-1 channels indirectly mediates adenosine fibrogenic actions by favouring ATP release from human subcutaneous fibroblasts
“…Furthermore, in cultured cells caffeine prevented A 2A receptor‐dependent Tcf21 and Ccn2 upregulation. These findings complement an existing body of literature describing the roles of A 2A receptors in fibrogenesis (Herman‐de‐Sousa et al, 2022; Kim et al, 2022; Perez‐Aso et al, 2014; Shaikh et al, 2016; J. Zhang et al, 2017) and the effects of caffeine on tissue fibrosis. For instance, caffeine has been reported to inhibit the activation of BHK‐21 kidney fibroblasts induced by hypoxia (Nilnumkhum et al, 2019) and it has also been reported to attenuate fibrosis of the liver (Modi et al, 2010; Shan et al, 2022) and lungs (Tatler et al, 2016).…”
Section: Discussionsupporting
confidence: 83%
“…Furthermore, in cultured cells caffeine prevented A 2A receptor-dependent Tcf21 and Ccn2 upregulation. These findings complement an existing body of literature describing the roles of A 2A receptors in fibrogenesis (Herman- de-Sousa et al, 2022;Kim et al, 2022;Perez-Aso et al, 2014;Shaikh et al, 2016;J. Zhang et al, 2017) and the effects of caffeine on tissue fibrosis.…”
Background and PurposeActivated 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 ApproachRNA 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 ResultsTranscription 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 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 up‐regulated in single Tcf21+ kidney fibroblasts, the most up‐regulated being Adgra2 and S1pr3. Adenosine receptors, Adora2a/2b, were up‐regulated 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 kidney samples.Conclusion and ImplicationsTcf21 is a marker of kidney fibroblasts that are enriched for fibrogenic genes in CKD. Further analysis of the GPCRs expressed by these cells may identify new targets for treating CKD.
“…Furthermore, in cultured cells caffeine prevented A 2A receptor‐dependent Tcf21 and Ccn2 upregulation. These findings complement an existing body of literature describing the roles of A 2A receptors in fibrogenesis (Herman‐de‐Sousa et al, 2022; Kim et al, 2022; Perez‐Aso et al, 2014; Shaikh et al, 2016; J. Zhang et al, 2017) and the effects of caffeine on tissue fibrosis. For instance, caffeine has been reported to inhibit the activation of BHK‐21 kidney fibroblasts induced by hypoxia (Nilnumkhum et al, 2019) and it has also been reported to attenuate fibrosis of the liver (Modi et al, 2010; Shan et al, 2022) and lungs (Tatler et al, 2016).…”
Section: Discussionsupporting
confidence: 83%
“…Furthermore, in cultured cells caffeine prevented A 2A receptor-dependent Tcf21 and Ccn2 upregulation. These findings complement an existing body of literature describing the roles of A 2A receptors in fibrogenesis (Herman- de-Sousa et al, 2022;Kim et al, 2022;Perez-Aso et al, 2014;Shaikh et al, 2016;J. Zhang et al, 2017) and the effects of caffeine on tissue fibrosis.…”
Background and PurposeActivated 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 ApproachRNA 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 ResultsTranscription 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 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 up‐regulated in single Tcf21+ kidney fibroblasts, the most up‐regulated being Adgra2 and S1pr3. Adenosine receptors, Adora2a/2b, were up‐regulated 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 kidney samples.Conclusion and ImplicationsTcf21 is a marker of kidney fibroblasts that are enriched for fibrogenic genes in CKD. Further analysis of the GPCRs expressed by these cells may identify new targets for treating CKD.
“…6 B). This was observed even when CGS21680 was used in the 3 to 10 nM concentration range that is known to be effective in other mesenchymal-originated cells, like subcutaneous fibroblasts and bone-marrow osteoblast progenitors [ 12 , 22 ]. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…The resulting cell suspensions were cultured and maintained under the same conditions as mentioned above. All the experiments were performed in the first subculture [ 13 , 14 , 20 – 22 ].…”
Section: Methodsmentioning
confidence: 99%
“…CGS21680, NECA, PSB603, and SCH442416 were diluted in dimethyl sulfoxide (DMSO); all other drugs were prepared in distilled water. Regarding solutions storage (as frozen aliquots at −20 °C) and dilution, pH control, and DMSO (maximum 0.05% v/v) testing, we followed that described in previous publications from our group [ 21 , 22 ].…”
Sustained pressure overload and fibrosis of the right ventricle (RV) are the leading causes of mortality in pulmonary arterial hypertension (PAH). Although the role of adenosine in PAH has been attributed to the control of pulmonary vascular tone, cardiac reserve, and inflammatory processes, the involvement of the nucleoside in RV remodelling remains poorly understood. Conflicting results exist on targeting the low-affinity adenosine A2B receptor (A2BAR) for the treatment of PAH mostly because it displays dual roles in acute vs. chronic lung diseases. Herein, we investigated the role of the A2BAR in the viability/proliferation and collagen production by cardiac fibroblasts (CFs) isolated from RVs of rats with monocrotaline (MCT)-induced PAH. CFs from MCT-treated rats display higher cell viability/proliferation capacity and overexpress A2BAR compared to the cells from healthy littermates. The enzymatically stable adenosine analogue, 5′-N-ethylcarboxamidoadenosine (NECA, 1–30 μM), concentration-dependently increased growth, and type I collagen production by CFs originated from control and PAH rats, but its effects were more prominent in cells from rats with PAH. Blockage of the A2BAR with PSB603 (100 nM), but not of the A2AAR with SCH442416 (100 nM), attenuated the proliferative effect of NECA in CFs from PAH rats. The A2AAR agonist, CGS21680 (3 and 10 nM), was virtually devoid of effect. Overall, data suggest that adenosine signalling via A2BAR may contribute to RV overgrowth secondary to PAH. Therefore, blockage of the A2AAR may be a valuable therapeutic alternative to mitigate cardiac remodelling and prevent right heart failure in PAH patients.
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