Impact of genetic background on nephropathy in diabetic mice

Abstract

With the goal of identifying optimal platforms for developing better models of diabetic nephropathy in mice, we compared renal effects of streptozotocin (STZ)-induced diabetes among five common inbred mouse strains (C57BL/6, MRL/Mp, BALB/c, DBA/2, and 129/SvEv). We also evaluated the renal consequences of chemical and genetic diabetes on the same genetic background (C57BL/6). There was a hierarchical response of blood glucose level to the STZ regimen among the strains (DBA/2 > C57BL/6 > MRL/MP > 129/SvEv > BALB/c). In all five strains, males demonstrated much more robust hyperglycemia with STZ than females. STZ-induced diabetes was associated with modest levels of albuminuria in all of the strains but was greatest in the DBA/2 strain, which also had the most marked hyperglycemia. Renal structural changes on light microscopy were limited to the development of mesangial expansion, and, while there were some apparent differences among strains in susceptibility to renal pathological changes, there was a significant positive correlation between blood glucose and the degree of mesangial expansion, suggesting that most of the variability in renal pathological abnormalities was because of differences in hyperglycemia. Although the general character of renal involvement was similar between chemical and genetic diabetes, Akita mice developed more marked hyperglycemia, elevated blood pressures, and less variability in renal structural responses. Thus, among the strains and models tested, the DBA/2 genetic background and the Akita (Ins2(+/C96Y)) model may be the most useful platforms for model development.

Deficiency of Endothelial Nitric-Oxide Synthase Confers Susceptibility to Diabetic Nephropathy in Nephropathy-Resistant Inbred Mice

“…21,32 The findings clearly demonstrate that reduced eNOS activity enhances glomerular injury in the setting of diabetes, supporting human studies suggesting that eNOS polymorphism and reduced eNOS activity are associated with accelerated diabetic nephropathy.…”

“…Among the inbred strains tested, C57BL/6 strain mice were shown to be resistant to nephropathy (albuminuria). 21,32 Importantly, the present study has demonstrated that insufficient eNOS activity may alter susceptibility of C57BL6 mouse to diabetic glomerular injury, indicating a vital role of eNOS in the development of diabetic nephropathy. Our results in mice support the finding in human diabetes that a predisposition for development of nephropathy is closely associated with eNOS polymorphisms.…”

Glomerular Localization and Expression of Angiotensin-Converting Enzyme 2 and Angiotensin-Converting Enzyme

“…These authors found that deletion of the Ace2 gene was associated with the development of albuminuria over time (12 mo of age) in male but not in female mice. In general, it is more difficult to produce albuminuria in female than in male mice (14,25). In this respect, it is noteworthy that in this study we used female db/db mice, because we were not aware of the findings of Oudit et al, which were published just recently (23).…”

Local overexpression of interleukin-1 family, member 6 relates to the development of tubulointerstitial lesions

“…14,15 Briefly, diabetes was induced with intraperitoneal injections of STZ (Calbiochem, San Diego, CA, USA) dissolved in 0.05 M sodium citrate buffer (pH 4.5). Mice received two rounds of injections of 40 mg/(kg day) STZ for 5 consecutive days, first at 8 weeks of age, and then, at 12.…”