Abstract 24: Tubular Vegfa is Required for Renal Microvasculature and Oxygen Sensing

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Abstract

Adequate renal oxygenation is pivotal for maintaining essential functions of the kidney. Vascular endothelial growth factor A (VEGFA) plays a key role in vascular formation and maintenance, processes that are critical for sufficient tissue perfusion and oxygenation. Here we show that Vegfa is expressed in select tubular epithelial cells within the nephron, while expression of its receptor (Kdr/Vegfr2) is restricted largely to capillary beds. Early genetic ablation of tubular Vegfa allows the formation of a grossly normal kidney. However, microvascular density is markedly reduced, leading to increased renal hypoxia. As a consequence the mice develop pronounced polycythemia (81 ± 1.62 vs. 58 ± 0.87 % Hematocrit), due to an increase in serum erythropoietin concentration (426.5 ± 49.3 vs. 249.3 ± 13.6 pg/ml). The elevation in circulating erythropoietin is elicited by an augmented renal production of the hormone, and occurs independent of changes in hepatic expression. In kidney, expression of classical hypoxia-inducible factor-1 responsive transcripts remains unaltered; suggesting that erythropoiesis partly compensates the capillary rarefaction. An increase in diastolic blood pressure (DBP, 112 ± 3.7 vs. 104 ± 1.6 mmHg) is present in mice lacking tubular Vegfa maintained on a normal diet, while systolic blood pressure (SBP, 139 ± 2.8 vs. 135 ± 2.8 mmHg) does not change. The difference in diastolic pressure is ablated when dietary NaCl content changed (DBP: 107 ± 3.1 vs. 103 ± 2.7 mmHg; SBP: 132 ± 4.1 vs. 131 ± 2.9 mmHg; for low NaCl), or when angiotensin II is infused (DBP: 137 ± 6.7 vs. 134 ± 3.8 mmHg; SBP: 161 ± 7.6 vs. 162 ± 9.3 mmHg). Moreover, renal electrolyte excretion remains unperturbed by reductions in tubular Vegfa. In conclusion, tubular Vegfa is critical for adequate development of renal microvasuculature, a prerequisite for proper oxygenation of the kidney. Compensatory polycythemia likely prevents severe perturbations of renal function in this model. In addition, increased diastolic blood pressure may occur as a consequence of capillary rarefaction within the kidney.

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