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 sex‐associated 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 albumin‐to‐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.
Highlights
The progressive rise in diabetes mellitus worldwide is paralleled by severe complications including retinopathy, neuropathy, and nephropathy (Valencia & Florez, 2017; Zhou et al, 2016)
40% of diabetic patients develop diabetic nephropathy (DN) (Reutens, 2013; Saran et al, 2018), which is characterized by albuminuria and loss of kidney function (Alicic, Rooney, & Tuttle, 2017; Reutens, 2013)
Renal collagen III levels were significantly increased in female UNx db/db mice compared with female sham db/+ controls (21.7 ± 1.1 Sham db/+ vs. 27.1 ± 0.9 mg UNx db/db females, p < .01, Figure 2d), whereas no statistically significant change was found in male UNx db/db mice versus male sham db/+ controls (p = .35)
Summary
The progressive rise in diabetes mellitus worldwide is paralleled by severe complications including retinopathy, neuropathy, and nephropathy (Valencia & Florez, 2017; Zhou et al, 2016). Except for the recent emergence of SGLT2 inhibitors and GLP-1 receptor agonists (Hocher & Tsuprykov, 2017) for nephroprotection in patients with diabetes, the DN therapeutic landscape has remained largely unchanged in the past 25 years (Johnson & Spurney, 2015; Wanner et al, 2016) This gap is largely due to the absence of reliable markers of disease risk and progression, as well as an incomplete understanding of the underlying mechanisms of DN in preclinical models and man. The db/db mouse which carries a homozygous inactivating leptin receptor mutation resulting in defective leptin signalling (Chen et al, 1996; Lee et al, 1996) and hyperphagia, obesity, insulin resistance, and hyperglycaemia (Lee & Bressler, 1981) have been extensively utilized (Tesch & Lim, 2010) These mice develop many of the pathological features of early human DN, including albuminuria and mesangial matrix expansion (Cohen, Lautenslager, & Shearman, 2001), but only mild glomerulosclerosis. We compared the progression of DN in male and female UNx db/db C57BLKS mice using standard biochemical and histological endpoints, as well as renal cortex transcriptomic changes
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