Impact of sex on diabetic nephropathy and the renal transcriptome in UNx db/db C57BLKS mice

Abstract

Diabetic nephropathy (DN) is associated with albuminuria and loss of kidney function and is the leading cause of end-stage renal disease. Despite evidence of sexassociated differences in the progression of DN in human patients, male mice are predominantly being used in preclinical DN research and drug development. Here, we compared renal changes in male and female uninephrectomized (UNx) db/db C57BLKS mice using immunohistochemistry and RNA sequencing. Male and female UNx db/db mice showed similar progression of type 2 diabetes, as assessed by obesity, hyperglycemia, and HbA1c. Progression of DN was also similar between sexes as assessed by kidney and glomerular hypertrophy as well as urine albuminto-creatinine ratio being increased in UNx db/db compared with control mice. In contrast, kidney collagen III and glomerular collagen IV were increased only in female UNx db/db as compared with respective control mice but showed a similar tendency in male UNx db/db mice. Comparison of renal cortex transcriptomes by RNA sequencing revealed 66 genes differentially expressed (p < .01) in male versus female UNx db/db mice, of which 9 genes were located on the sex chromosomes. In conclusion, male and female UNx db/db mice developed similar hallmarks of DN pathology, suggesting no or weak sex differences in the functional and structural changes during DN progression. K E Y W O R D S albuminuria, animal model, diabetic nephropathy, mesangial expansion, uninephrectomy How to cite this article: Sembach FE, Fink LN, Johansen T, et al. Impact of sex on diabetic nephropathy and the renal transcriptome in UNx db/ db C57BLKS mice. Physiol Rep. 2019;7:e14333.

Dual hit rat models of diabetic cardiomyopathy and nephropathy: pancreatectomy combined with isoprenaline treatment or uninephrectomy

“…Podocin/type IV collagen double fluorescent immunohistochemical staining of kidney sections was performed as previously described [22].…”

“…The collagen area fraction was calculated as the Picro Sirius Red area divided by the total tissue area. Intra-glomerular collagen type 4 content and stereological estimation of kidney compartmental volumes were determined as previously described [22].…”

“…Some of these commonly-used models of diabetes, e.g. streptozotocin-treatment (STZ) and the db/db genetic mouse model, have previously been combined with angiotensin II or uninephrectomy to mimic and accelerate DbCM or DN, respectively [21][22][23].…”

Rat pancreatectomy combined with isoprenaline or uninephrectomy as models of diabetic cardiomyopathy or nephropathy

“…Sections were counterstained in Mayer's hematoxylin and cover slipped with Pertex. Podocin/ type IV collagen double fluorescent immunohistochemical staining of kidney sections was performed as previously described 22 .…”

“…The collagen area fraction was calculated as the Picro Sirius Red area divided by the total tissue area. Intra-glomerular collagen type 4 content and stereological estimation of kidney compartmental volumes were determined as previously described 22 Statistical analysis. Except for the gene expression data set, which was analysed using DEseq2 package for R with default parameters 40 , all data were analyzed using GraphPad Prism software (version 8.2).…”