Perivascular CD73⁺cells attenuate inflammation and interstitial fibrosis in the kidney microenvironment

Abstract

Progressive tubulointerstitial fibrosis may occur after acute kidney injury due to persistent inflammation. Purinergic signaling by 5′-ectonucleotidase, CD73, an enzyme that converts AMP to adenosine on the extracellular surface, can suppress inflammation. The role of CD73 in progressive kidney fibrosis has not been elucidated. We evaluated the effect of deletion of CD73 from kidney perivascular cells (including pericytes and/or fibroblasts of the Foxd1+ lineage) on fibrosis. Perivascular cell expression of CD73 was necessary to suppress inflammation and prevent kidney fibrosis in Foxd1CreCD73fl/fl mice evaluated 14 days after unilateral ischemia-reperfusion injury or folic acid treatment (250 mg/kg). Kidneys of Foxd1CreCD73fl/fl mice had greater collagen deposition, expression of proinflammatory markers (including various macrophage markers), and platelet-derived growth factor recepetor-β immunoreactivity than CD73fl/fl mice. Kidney dysfunction and fibrosis were rescued by administration of soluble CD73 or by macrophage deletion. Isolated CD73−/− kidney pericytes displayed an activated phenotype (increased proliferation and α-smooth muscle actin mRNA expression) compared with wild-type controls. In conclusion, CD73 in perivascular cells may act to suppress myofibroblast transformation and influence macrophages to promote a wound healing response. These results suggest that the purinergic signaling pathway in the kidney interstitial microenvironment orchestrates perivascular cells and macrophages to suppress inflammation and prevent progressive fibrosis.

Neural transcription factor Pou4f1 promotes renal fibrosis via macrophage–myofibroblast transition

“…In addition, our microarray data found up-regulation of Pdgfb, Pdgfrb, and integrins in TGF-β-stimulated BMDMs. This is consistent with the MMT process and with previous studies showing that macrophages are a source of profibrogenic factors that can promote myofibroblast transition from perivascular cells in the injured kidney (32). Thus, while Pou4f1 can stimulate renal fibrosis directly through MMT, it may also be the case that Pou4f1 can indirectly promote renal fibrosis by inducing macrophage production of profibrotic factors.…”

Role of α2-Adrenoceptors in Hypertension: Focus on Renal Sympathetic Neurotransmitter Release, Inflammation, and Sodium Homeostasis

“…Additionally to the pleiotropic effects of ATP on its P2 (purinergic type 2) receptors in the kidney (Solini et al, 2015), ATP can also be sequentially hydrolyzed by CD93 to ADP and AMP with AMP being further converted to adenosine by CD73. Alterations in the balance of nucleotides to nucleosides have major impacts on renal function, the development of hypertension, renal fibrosis, and inflammation (for a better overview, please refer to Kishore et al, 2018;Perry et al, 2019).…”

Long Non-coding RNA: An Emerging Contributor and Potential Therapeutic Target in Renal Fibrosis

“…Renal fibrosis (RF) is a universal pathological process that leads to terminal renal failure in chronic kidney disease (CKD) (Sun et al, 2016); it is induced in response to diverse factors, such as external injury, inflammation, ischemia, hypoxia, myofibroblast activation and migration, and matrix deposition and remodeling (Liu et al, 2017;Humphreys, 2018;Bijkerk et al, 2019;Perry et al, 2019;. Many diseases are associated with RF development, including obstructive kidney disease, chronic glomerulonephritis, chronic pyelonephritis, systemic lupus erythematosus nephropathy, and hereditary nephropathies, such as Alport syndrome, diabetic nephropathy (DN), hypertensive nephropathy, and drug-induced nephropathy (González et al, 2008;Davidson, 2016;Seccia et al, 2017).…”