Abstract
Clinical studies indicate that sex differences exist in susceptibility for developing diabetic kidney disease (DKD), supporting the need to examine both sexes in animal studies of DKD. Streptozotocin (STZ) is commonly used in male mice to induce diabetes and DKD. However, females are not normally included because their sex hormones partially protect them from STZ‐induced islet injury and consequent diabetes. To address this issue, we identified a strategy to induce comparable diabetes in male and female mice using STZ and determined whether both sexes develop equivalent renal injury. Male and female mice lacking the gene for endothelial nitric oxide synthase (Nos3‐/‐) were made diabetic with five or six low‐dose STZ injections, respectively. Groups of male and female mice with equivalent hyperglycemia at week 3 after STZ were assessed for DKD at week 8. STZ‐treated male and female Nos3‐/‐ mice maintained comparable hyperglycemia between weeks 3 and 8 had an equivalent increase in HbA1c levels and comparable hypertension. Urine albumin/creatinine levels were elevated eightfold in mice of both sexes at week 8, accompanied by an equivalent loss of podocytes. In diabetic males and females, plasma cystatin C levels and glomerular collagen deposition were similarly increased. Kidney mRNA levels of proinflammatory and profibrotic markers and kidney injury molecule‐1 (KIM‐1) were equally elevated in males and females, indicating comparable kidney injury. This study shows that equivalent diabetes induces a comparable onset of DKD in male and female Nos3‐/‐ mice, demonstrating that it is possible to include males and females together in studies of DKD.
Highlights
Diabetic kidney disease (DKD) is the most prevalent cause of end-stage kidney disease (ESKD) affecting both men and women (Harjutsalo and Groop, 2014)
These findings indicate that optimal clinical treatment of patients with DKD may require a better understanding of potential sex differences in disease a 2019 The Authors
Analysis of blood at week 8 found that levels of HbA1c were the same in male and female diabetic mice (Fig. 2), demonstrating that equivalent diabetes had been achieved in both sexes
Summary
Diabetic kidney disease (DKD) is the most prevalent cause of end-stage kidney disease (ESKD) affecting both men and women (Harjutsalo and Groop, 2014). Female rodents appear more resistant to type 2 diabetes, because food intake is usually higher in males which is associated with earlier increases in blood glucose and earlier declines in insulin (Chow et al 2004; Ohta et al 2014) These sex differences have resulted in a failure to adequately compare the development of DKD in males and females in experimental animal models and to compare the outcomes of therapeutic interventions in both sexes. Diabetic Nos3-/mice develop substantial albuminuria, kidney inflammation, nodular glomerulosclerosis, and renal function impairment which resembles progressive DKD in patients (Zhao et al 2006; Nakagawa et al 2007; Takahashi and Harris, 2014) This model meets the pathological feature requirements put forward by NIDDK sponsored Diabetes Complications Consortium (www.diacomp.org) which identifies a models’ suitability for experimental studies of DKD.
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