title: Maintenance of vascular integrity by pericytes is essential for normal kidney function.
abstract: Pericytes are tissue-resident mesenchymal progenitor cells anatomically associated with the vasculature that have been shown to participate in tissue regeneration. Here, we tested the hypothesis that kidney pericytes, derived from FoxD1+mesodermal progenitors during embryogenesis, are necessary for postnatal kidney homeostasis. Diphtheria toxin delivery to FoxD1Cre::RsDTR transgenic mice resulted in selective ablation of >90% of kidney pericytes but not other cell lineages. Abrupt increases in plasma creatinine, blood urea nitrogen, and albuminuria within 96 h indicated acute kidney injury in pericyte-ablated mice. Loss of pericytes led to a rapid accumulation of neutral lipid vacuoles, swollen mitochondria, and apoptosis in tubular epithelial cells. Pericyte ablation led to endothelial cell swelling, reduced expression of vascular homeostasis markers, and peritubular capillary loss. Despite the observed injury, no signs of the acute inflammatory response were observed. Pathway enrichment analysis of genes expressed in kidney pericytes in vivo identified basement membrane proteins, angiogenic factors, and factors regulating vascular tone as major regulators of vascular function. Using novel microphysiological devices, we recapitulated human kidney peritubular capillaries coated with pericytes and showed that pericytes regulate permeability, basement membrane deposition, and microvascular tone. These findings suggest that through the active support of the microvasculature, pericytes are essential to adult kidney homeostasis.
authors.affiliation: Research and Development, Biogen, Cambridge, Massachusetts.
authors.forename: Dario R
authors.initials: DR
authors.lastname: Lemos
authors.affiliation: Research and Development, Biogen, Cambridge, Massachusetts.
authors.forename: Graham
authors.initials: G
authors.lastname: Marsh
authors.affiliation: Research and Development, Biogen, Cambridge, Massachusetts.
authors.forename: Angela
authors.initials: A
authors.lastname: Huang
authors.affiliation: Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Campanholle
authors.affiliation: Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: Takahide
authors.initials: T
authors.lastname: Aburatani
authors.affiliation: Research and Development, Biogen, Cambridge, Massachusetts.
authors.forename: Lan
authors.initials: L
authors.lastname: Dang
authors.affiliation: Research and Development, Biogen, Cambridge, Massachusetts.
authors.forename: Ivan
authors.initials: I
authors.lastname: Gomez
authors.affiliation: Nortis Incorporated, Seattle, Washington; and.
authors.forename: Ken
authors.initials: K
authors.lastname: Fisher
authors.affiliation: Research and Development, Biogen, Cambridge, Massachusetts.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ligresti
authors.affiliation: Department of Physiology, University of Southern California, Los Angeles, California.
authors.forename: Janos
authors.initials: J
authors.lastname: Peti-Peterdi
authors.affiliation: Research and Development, Biogen, Cambridge, Massachusetts; jeremy.duffield@biogen.com jeremysd@u.washington.edu.|Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duffield
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism*; D000818:Animals; D002196:Capillaries / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D055806:Microvessels / Q000378:metabolism; D020286:Pericytes / Q000378:metabolism*; D010539:Permeability
keywords: acute kidney injury; endothelium; microfluidics; pericyte