Link between reduced nephron number and hypertension: studies in a mutant mouse model

Low birth weight (LBW) infants with reduced nephron numbers have significantly increased risk for hypertension later in life, which is a devastating health problem. The risk from a reduction in nephron number alone is not clear. Recently, using conditional knock-out approach, we have developed a mutant mouse with reduced nephron number in utero and no change in birth weight, by deleting fibroblast growth factor receptor 2 (fgfr2) in the ureteric bud. Our purpose was to investigate the role of in utero reduced nephron number alone in absence of LBW as a risk for developing hypertension in adulthood. Using tail cuff blood pressure measurements we observed significant increases in systolic blood pressure in one year old mutant mice versus controls. We also detected cardiac end-organ injury from hypertension as shown by significant increases in normalized heart weights, left ventricular (LV) wall thickness, and LV tissue area. Two-dimensional echocardiography revealed no changes in cardiac output and therefore significant increases in systemic vascular resistance in mutants versus controls. We also observed increases in serum blood urea nitrogen (BUN) levels and histologic evidence of glomerular and renal tubular injury in mutant mice versus controls. Thus, these studies suggest that our mutant mice may serve as a relevant model to study the link between reduction of nephron number in utero and the risk of hypertension and chronic renal failure in adulthood.