Abstract
There is strong evidence from human and animal models that exposure to maternal hyperglycemia during in utero development can detrimentally affect fetal kidney development. Notwithstanding this knowledge, the precise effects of diabetic pregnancy on the key processes of kidney development are unclear due to a paucity of studies and limitations in previously used methodologies. The purpose of the present study was to elucidate the effects of hyperglycemia on ureteric branching morphogenesis and nephrogenesis using unbiased techniques. Diabetes was induced in pregnant C57Bl/6J mice using multiple doses of streptozotocin (STZ) on embryonic days (E) 6.5-8.5. Branching morphogenesis was quantified ex vivo using Optical Projection Tomography, and nephrons were counted using unbiased stereology. Maternal hyperglycemia was recognised from E12.5. At E14.5, offspring of diabetic mice demonstrated fetal growth restriction and a marked deficit in ureteric tip number (control 283.7±23.3 vs. STZ 153.2±24.6, mean±SEM, p<0.01) and ureteric tree length (control 33.1±2.6 mm vs. STZ 17.6±2.7 mm, p = 0.001) vs. controls. At E18.5, fetal growth restriction was still present in offspring of STZ dams and a deficit in nephron endowment was observed (control 1246.2±64.9 vs. STZ 822.4±74.0, p<0.001). Kidney malformations in the form of duplex ureter and hydroureter were a common observation (26%) in embryos of diabetic pregnancy compared with controls (0%). Maternal insulin treatment from E13.5 normalised maternal glycaemia but did not normalise fetal weight nor prevent the nephron deficit. The detrimental effect of hyperglycemia on ureteric branching morphogenesis and, in turn, nephron endowment in the growth-restricted fetus highlights the importance of glycemic control in early gestation and during the initial stages of renal development.
Highlights
The global prevalence of diabetes in pregnancy is increasing, both in terms of gestational diabetes mellitus and pre-existing type 1 and 2 diabetes mellitus [1,2]
While nephron endowment is highly dependent on adequate ureteric branching morphogenesis, to date the effect of hyperglycemia on ureteric tree development has not been assessed in vivo
STZ increases maternal blood glucose concentrations from E12.5 leading to offspring growth restriction and reduced ureteric tree development at E14.5
Summary
The global prevalence of diabetes in pregnancy is increasing, both in terms of gestational diabetes mellitus (first diagnosis of diabetes in pregnancy) and pre-existing type 1 and 2 diabetes mellitus [1,2]. Assessment of ureteric branching morphogenesis typically involved culturing fetal kidneys for a number of days in vitro. This procedure results in a flattened kidney that can be wholemount immunostained and imaged. Previous in vitro culture studies have been limited to measures of ureteric tip number and have produced inconsistent results [16,19,20]. These discrepancies are likely the result of variability inherent to culture preparations, differences in the length of culture time and the type of media and supplements used. A better understanding of the effect of hyperglycemia on ureteric branching morphogenesis, and in turn nephrogenesis, is required
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