The Gne M712T mouse as a model for human glomerulopathy.
Pathological glomerular hyposialylation has been implicated in certain unexplained glomerulopathies, including minimal change nephrosis, membranous glomerulonephritis, and IgA nephropathy. We studied our previously established mouse model carrying a homozygous mutation in the key enzyme of sialic acid biosynthesis, N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. Mutant mice died before postnatal day 3 (P3) from severe glomerulopathy with podocyte effacement and segmental glomerular basement membrane splitting due to hyposialylation. Administration of the sialic acid precursor N-acetylmannosamine (ManNAc) led to improved sialylation and survival of mutant pups beyond P3. We determined the onset of the glomerulopathy in the embryonic stage. A lectin panel, distinguishing normally sialylated from hyposialylated glycans, used WGA, SNA, PNA, Jacalin, HPA, and VVA, indicating glomerular hyposialylation of predominantly O-linked glycoproteins in mutant mice. The glomerular glycoproteins nephrin and podocalyxin were hyposialylated in this unique murine model. ManNAc treatment appeared to ameliorate the hyposialylation status of mutant mice, indicated by a lectin histochemistry pattern similar to that of wild-type mice, with improved sialylation of both nephrin and podocalyxin, as well as reduced albuminuria compared with untreated mutant mice. These findings suggest application of our lectin panel for categorizing human kidney specimens based on glomerular sialylation status. Moreover, the partial restoration of glomerular architecture in ManNAc-treated mice highlights ManNAc as a potential treatment for humans affected with disorders of glomerular hyposialylation.
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892-1851, USA.
Sravan
S
Kakani
Tal
T
Yardeni
Justin
J
Poling
Carla
C
Ciccone
Terren
T
Niethamer
Enriko D
ED
Klootwijk
Irini
I
Manoli
Daniel
D
Darvish
Shelley
S
Hoogstraten-Miller
Patricia
P
Zerfas
E
E
Tian
Kelly G
KG
Ten Hagen
Jeffrey B
JB
Kopp
William A
WA
Gahl
Marjan
M
Huizing
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002238:Carbohydrate Epimerases / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006595:Hexosamines / Q000627:therapeutic use; D006801:Humans; D007674:Kidney Diseases / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000196:embryology / Q000378:metabolism / Q000648:ultrastructure; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D009154:Mutation; D019158:N-Acetylneuraminic Acid / Q000502:physiology; D050199:Podocytes / Q000378:metabolism / Q000648:ultrastructure; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012795:Sialoglycoproteins / Q000378:metabolism
D015415:Biomarkers; D002352:Carrier Proteins; D006595:Hexosamines; D008565:Membrane Proteins; D012795:Sialoglycoproteins; C113267:nephrin; C001643:podocalyxin; D002238:Carbohydrate Epimerases; C024519:N-acyl-D-glucosamine 2-epimerase; D019158:N-Acetylneuraminic Acid; C002022:N-acetylmannosamine