BTBR Ob/Ob mutant mice model progressive diabetic nephropathy.
Authors Hudkins KL, Pichaiwong W, Wietecha T, Kowalewska J, Banas MC, Spencer MW,
Mühlfeld A, Koelling M, Pippin JW, Shankland SJ, Askari B, Rabaglia ME, Keller
MP, Attie AD, Alpers CE
Submitted By Charles Alpers on 9/29/2010
Status Published
Journal Journal of the American Society of Nephrology : JASN
Year 2010
Date Published 9/1/2010
Volume : Pages 21 : 1533 - 1542
PubMed Reference 20634301
Abstract 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.

Investigators with authorship
Charles AlpersUniversity of Washington