BTBR Ob/Ob Mutant Mice Model Progressive Diabetic Nephropathy

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 Ͼ50% 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. Diabetic nephropathy (DN) is the largest single cause of ESRD in the United States, accounting for nearly half of the patients who enter the dialysis patient population each year and currently accounting for 45% of prevalent kidney failure in the United States. 1-4 Although both type 1 and type 2 diabetes lead to DN, the current epidemic of DN is due to type 2 diabetes; however, understanding the mechanisms that produce the constellation of clinical and pathologic alterations that define DN in humans remains very incomplete, in part because clinical DN is a slowly progressive disease, and relevant animal models that produce this constellation of pathologic and clinical abnormalities have important limitations. Mice rendered hyperglycemic by administration of streptozotocin (STZ) or through genetic predisposition such as the db/db mouse can develop some features of DN, most notably glomerular mesangial expansion, but do so only over prolonged periods and do not progress to ESRD. [5][6][7][8][9] Most murine models to date have failed to develop reliably marked mesangial expansion or the

B7–1 Is Not Induced in Podocytes of Human and Experimental Diabetic Nephropathy

“…We analyzed kidneys from 20-to 22-week-old BTBR ob/ob mice, a model of type 2 diabetes. 28 Wild-type (WT) mice displayed faint spotted glomerular B7-1 expression (Figure 2, A and A9), similar to that found in the glomeruli of BTBR ob/ob mice ( Figure 2, B and B9). No signal was observed in negative control sections incubated with the secondary antibody alone [Supplemental Figure 2B(-)].…”

Urinary peptidomics provides a noninvasive humanized readout of diabetic nephropathy in mice

“…While a multitude of animal models of DN exist 11 , the most frequently used models of T2D DN are the BTBRob/ob mice 12 and uninephrectomized db/db mice on a C57BLKS background (UNxdb/db, 11 ). These two models are obese insulin resistant DN models due to leptin or leptin receptor deficiency respectively, displaying renal features similar to that observed in humans, including progressive albuminuria with advanced glomerular lesions and mild focal interstitial fibrosis.…”

Methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism and diabetic nephropathy susceptibility in patients with type 2 diabetes mellitus

“…[6][7][8] Although both type 1 and type 2 diabetes are able to induce DN, the current DN epidemic has been shown to be predominantly associated with type 2 diabetes. 9 However, a fundamental understanding of the interplay between degenerate biological mechanisms in humans and exogenous influences that produce the clinical and pathologic alterations observed in DN remains incomplete. Next to environmental and life-style stressors, the susceptibility to DN has an intrinsic genetic basis, which is demonstrated by familial aggregation and ethnic-specific prevalence rates, and appears to be the most prominent in African-Americans and Pima Indians.…”