Regardless of etiology, progressive renal disease causes ultrastructural and functional alterations of peritubular capillaries.
Progressive renal diseases are associated with rarefaction of peritubular capillaries, but the ultrastructural and functional alterations of the microvasculature are not well described. To study this, we analyzed different time points during progressive kidney damage and fibrosis in 3 murine models of different disease etiologies. These models were unilateral ureteral obstruction, unilateral ischemia-reperfusion injury, and Col4a3-deficient mice, we analyzed ultrastructural alterations in patient biopsy specimens. Compared with kidneys of healthy mice, we found a significant and progressive reduction of peritubular capillaries in all models analyzed. Ultrastructurally, compared with the kidneys of control mice, focal widening of the subendothelial space and higher numbers of endothelial vacuoles and caveolae were found in fibrotic kidneys. Quantitative analysis showed that peritubular capillary endothelial cells in fibrotic kidneys had significantly and progressively reduced numbers of fenestrations and increased thickness of the cell soma and lamina densa of the capillary basement membrane. Similar ultrastructural changes were also observed in patient's kidney biopsy specimens. Compared with healthy murine kidneys, fibrotic kidneys had significantly increased extravasation of Evans blue dye in all 3 models. The extravasation could be visualized using 2-photon microscopy in real time in living animals and was mainly localized to capillary branching points. Finally, fibrotic kidneys in all models exhibited a significantly greater degree of interstitial deposition of fibrinogen. Thus, peritubular capillaries undergo significant ultrastructural and functional alterations during experimental progressive renal diseases, independent of the underlying injury. Analyses of these alterations could provide read-outs for the evaluation of therapeutic approaches targeting the renal microvasculature.
Institute of Pathology, RWTH University of Aachen, Aachen, Germany; Division of Nephrology, RWTH University of Aachen, Aachen, Germany; Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia; Institute for Clinical and Translational Research, Biomedical Research Center SAS, Bratislava, Slovakia.
Janka
J
Bábíčková
Institute of Pathology, RWTH University of Aachen, Aachen, Germany.
Barbara M
BM
Klinkhammer
Institute of Pathology, RWTH University of Aachen, Aachen, Germany; Division of Nephrology, RWTH University of Aachen, Aachen, Germany.
Eva M
EM
Buhl
Institute of Pathology, RWTH University of Aachen, Aachen, Germany.
Sonja
S
Djudjaj
Institute of Pathology, RWTH University of Aachen, Aachen, Germany; Electron Microscopy Facility, RWTH University of Aachen, Aachen, Germany.
Mareike
M
Hoss
Division of Gastroenterology, RWTH University of Aachen, Aachen, Germany.
Felix
F
Heymann
Division of Gastroenterology, RWTH University of Aachen, Aachen, Germany.
Frank
F
Tacke
Division of Nephrology, RWTH University of Aachen, Aachen, Germany.
Jürgen
J
Floege
Institute of Pathology, University Hospital Cologne, Cologne, Germany.
Jan U
JU
Becker
Institute of Pathology, RWTH University of Aachen, Aachen, Germany; Division of Nephrology, RWTH University of Aachen, Aachen, Germany. Electronic address: pboor@ukaachen.de.
Peter
P
Boor
D000818:Animals; D001485:Basement Membrane / Q000098:blood supply / Q000473:pathology; D001706:Biopsy; D002196:Capillaries / Q000473:pathology* / Q000648:ultrastructure; D004195:Disease Models, Animal; D018450:Disease Progression; D042783:Endothelial Cells / Q000473:pathology* / Q000648:ultrastructure; D005355:Fibrosis; D006801:Humans; D007150:Immunohistochemistry; D007674:Kidney Diseases / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D007684:Kidney Tubules / Q000098:blood supply* / Q000166:cytology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation; D008855:Microscopy, Electron, Scanning; D036641:Microscopy, Fluorescence, Multiphoton; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D015427:Reperfusion Injury / Q000150:complications; D013997:Time Factors; D014517:Ureteral Obstruction / Q000150:complications
C535066:Col4a3bp protein, mouse; D017346:Protein Serine-Threonine Kinases
chronic kidney disease; endothelial cells; endothelial dysfunction; leakage; microvasculature; ultrastructure