BTBR Ob/Ob mutant mice model progressive diabetic nephropathy.
There remains a need for robust mouse models of diabetic nephropathy (DN) that mimic key features of advanced human DN. The recently developed mouse strain BTBR with the ob/ob leptin-deficiency mutation develops severe type 2 diabetes, hypercholesterolemia, elevated triglycerides, and insulin resistance, but the renal phenotype has not been characterized. Here, we show that these obese, diabetic mice rapidly develop morphologic renal lesions characteristic of both early and advanced human DN. BTBR ob/ob mice developed progressive proteinuria beginning at 4 weeks. Glomerular hypertrophy and accumulation of mesangial matrix, characteristic of early DN, were present by 8 weeks, and glomerular lesions similar to those of advanced human DN were present by 20 weeks. By 22 weeks, we observed an approximately 20% increase in basement membrane thickness and a >50% increase in mesangial matrix. Diffuse mesangial sclerosis (focally approaching nodular glomerulosclerosis), focal arteriolar hyalinosis, mesangiolysis, and focal mild interstitial fibrosis were present. Loss of podocytes was present early and persisted. In summary, BTBR ob/ob mice develop a constellation of abnormalities that closely resemble advanced human DN more rapidly than most other murine models, making this strain particularly attractive for testing therapeutic interventions.
Hudkins
Kelly L
KL
Department of Pathology, University of Washington, Seattle, Washington, USA.
Pichaiwong
Warangkana
W
Wietecha
Tomasz
T
Kowalewska
Jolanta
J
Banas
Miriam C
MC
Spencer
Min W
MW
Mühlfeld
Anja
A
Koelling
Mariko
M
Pippin
Jeffrey W
JW
Shankland
Stuart J
SJ
Askari
Bardia
B
Rabaglia
Mary E
ME
Keller
Mark P
MP
Attie
Alan D
AD
Alpers
Charles E
CE
D000818:Animals; D003928:Diabetic Nephropathies / Q000209:etiology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005355:Fibrosis; D037502:Galectin 3 / Q000032:analysis; D007333:Insulin Resistance; D007668:Kidney / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D050199:Podocytes / Q000473:pathology
D037502:Galectin 3