Megalin is an endocytic receptor highly expressed in the proximal tubules of the kidney. Recently, we demonstrated that this receptor is essential for the renal uptake and conversion of 25-OH vitamin D3 to 1,25-(OH)2 vitamin D3, a central step in vitamin D and bone metabolism. Unfortunately, the perinatal lethality of the conventional megalin knockout mouse model precluded the detailed analysis of the significance of megalin for calcium homeostasis and bone turnover in vivo. Here, we have generated a new mouse model with conditional inactivation of the megalin gene in the kidney by using Cre recombinase. Animals with a renal-specific receptor gene defect were viable and fertile. However, lack of receptor expression in the kidney results in plasma vitamin D deficiency, in hypocalcemia and in severe bone disease, characterized by a decrease in bone mineral content, an increase in osteoid surfaces, and a lack of mineralizing activity. These features are consistent with osteomalacia (softening of the bones) as a consequence of hypovitaminosis D and demonstrate the crucial importance of the megalin pathway for systemic calcium homeostasis and bone metabolism.
We studied the hemodynamic response of the isolated erythrocyte-perfused kidney to 25 min of ischemia and found that renal vascular resistance (RVR) was increased in the reflow period (16.7 +/- 1.4 mmHg.ml-1.min.g following ischemia vs. 10.2 +/- 0.8 mmHg.ml-1.min.g in control kidneys). Endothelial independent vasodilators [atrial natriuretic factor (ANF) and sodium nitroprusside] prevented the increase in RVR that occurred after ischemia. In contrast, acetylcholine and the calcium ionophore A23187, two vasodilators that act by releasing endothelium-derived relaxing factor (EDRF), had no effect on the increased RVR that occurs on reflow. Two inhibitors of EDRF, methylene blue and gossypol, increased RVR in nonischemic kidneys by 45 +/- 6 and 46 +/- 11%, respectively, an increase that was comparable to that found with ischemia alone (55 +/- 7%). The increase in RVR found with the combination of EDRF inhibition and ischemia (59 +/- 5%) was the same as that found with ischemia alone. We conclude that EDRF activity is impaired following ischemia and reperfusion. This abnormality in EDRF may be an important mechanism contributing to postischemic vasoconstriction in the renal vasculature.
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