Lack of {alpha}8-integrin aggravates podocyte injury in experimental diabetic nephropathy.
Development of diabetic nephropathy is accompanied by changes in integrin-mediated cell-matrix interactions. The α8-integrin chain is specifically expressed in mesangial cells of the glomerulus. During experimental hypertension, α8-integrin plays a protective role in the glomerulus. We hypothesized that α8-integrin is involved in maintaining the integrity of the glomerulus in diabetic nephropathy. Experimental streptozotocin (STZ) diabetes led to an increased expression and glomerular deposition of α8-integrin. To test the functional role of α8-integrin, STZ diabetes was induced in mice with a homozygous (α8-/-) or heterozygous (α8+/-) deletion of the α8-integrin gene and in wild-type litters (α8+/+). Blood glucose and mean arterial blood pressure were not different in α8-/- and α8+/+ mice after 6 wk of diabetes. However, diabetic α8-/- mice developed significantly higher albuminuria and more glomerulosclerosis than diabetic α8+/+ mice. Moreover, in diabetic α8-/- mice, the number of glomerular cells staining positive for the podocyte markers WT-1 and vimentin were reduced more prominently than in diabetic α8+/+. The filtration barrier protein nephrin was downregulated in diabetic glomeruli with the strongest reduction observed in α8-/- mice. Taken together, α8-/- mice developed more severe glomerular lesions and podocyte damage after onset of STZ diabetes than α8+/+ mice, indicating that α8-integrin is protective for the structure and function of the glomerulus and maintains podocyte integrity during the development of diabetic nephropathy.
Hartner
Andrea
A
Dept. of Pediatrics, Loschgestrasse 15, D-91054 Erlangen, Germany. andrea.hartner@uk-erlangen.de
Cordasic
Nada
N
Menendez-Castro
Carlos
C
Volkert
Gudrun
G
Yabu
Julie M
JM
Kupraszewicz-Hutzler
Miroslava
M
Rascher
Wolfgang
W
Hilgers
Karl F
KF
D000419:Albuminuria / Q000378:metabolism; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000473:pathology; D003928:Diabetic Nephropathies / Q000473:pathology*; D007150:Immunohistochemistry; D039001:Integrin alpha Chains / Q000235:genetics* / Q000502:physiology*; D007668:Kidney / Q000473:pathology; D007677:Kidney Function Tests; D007678:Kidney Glomerulus / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D042282:Microdissection; D009392:Nephrectomy; D050199:Podocytes / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D039001:Integrin alpha Chains; D008565:Membrane Proteins; D012333:RNA, Messenger; C093856:integrin alpha8; C113267:nephrin