Genetic modulation of diabetic nephropathy among mouse strains with Ins2Akitamutation

Abstract

Diabetic nephropathy (DN) is a major complication of diabetes and the leading cause of end‐stage renal disease. DN is characterized by changes in kidney structure and function but the underlying genetic and molecular factors are poorly understood. We used a mouse diversity panel to explore the genetic basis of DN traits in mice carrying the Ins2 Akita mutation. Twenty‐eight Akita strains were generated by breeding this panel to DBA/2.Akita mice. Male F1 diabetic and nondiabetic littermates were evaluated for DN‐related traits. Urine albumin‐to‐creatinine ratios (ACRs), volume and cystatin C as well as blood urea nitrogen and lipoprotein levels varied significantly among the diabetic strains. For most Akita strains, ACR values increased 2‐ to 6‐fold over euglycemic control values. However, six strains exhibited changes in ACR exceeding 10‐fold with two strains (NOD/ShiLt and CBA) showing 50‐ to 83‐ fold increases. These increases are larger than previously reported among available DN mouse models establishing these strains as useful for additional studies of renal function. ACRs correlated with cystatin C (P = 0.0286), a measure of hyperfiltration and an interstitial tubular marker associated with DN onset in humans suggesting that tubule damage as well as podocyte‐stress contributed to reduced kidney function assessed by ACR. Although large changes were seen for ACRs, severe nephropathology was absent. However, glomerular hypertrophy and collagen IV content were found to vary significantly among strains suggesting a genetic basis for early onset features of DN. Our results define the range of DN phenotypes that occur among common inbred strains of mice.

The Hybrid Mouse Diversity Panel: a resource for systems genetics analyses of metabolic and cardiovascular traits

“…In some studies, only a fraction of the number of strains required for association mapping of traits have been characterized. One such study involves analysis of kidney disease in the context of type 1 diabetes ( 53 ). The authors bred the DBA/2J.…”

“…Akita transgenic mouse model of type 1 diabetes to 28 of the HMDP strains and examined histologic and molecular parameters associated with diabetic nephropathy in diabetic mice and nondiabetic littermates. The most striking observed phenotype was urine albumin-to-creatinine ratios, which increased 2- to 6-fold over euglycemic control values for most strains, but more than 10-fold in six strains, including 50- and 83-fold in two strains, NOD/ShiLtJ and CBA/J, respectively ( 53 ).…”

Targeting Methylglyoxal in Diabetic Kidney Disease Using the Mitochondria-Targeted Compound MitoGamide

“…Picrosirius red staining was used to assess the degree of tubulointerstitial fibrosis. There was no significant difference in tubulointerstitial fibrosis across all groups, which is not surprising as the Akita mouse model bred onto the C57BL/6J background is known to not exhibit marked changes in the tubulointerstitium [ 42 ].…”

Urocortin 2 Gene Transfer Improves Glycemic Control and Reduces Retinopathy and Mortality in Murine Insulin Deficiency

“…Nephropathy in the Akita mouse depends upon what line the Ins2 Akita line is crossed with, and C57BL/6J tends to have minimal renal abnormalities. 20,27 The physiological mechanisms by which Ucn2 gene transfer affects glucose disposal resides primarily in its augmentation of skeletal muscle insulin sensitivity and subsequent glucose uptake in Akita mice, effects which were shown in hyperinsulinemic euglycemic clamp studies ( Figures 3G-3L). In addition, in Akita mice, Ucn2 gene transfer increased insulin release in vivo (Figure 4), owing to a direct effect of Ucn2 on islet insulin secretion ( Figure 4D).…”