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Hypocalcemia and osteopathy in mice with kidney-specific megalin gene defect
Jörg R Leheste1, Flemming Melsen, Maren Wellner
1Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany.
Abstract:
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.
Insights
Megalin in kidney proximal tubules is crucial for vitamin D activation and calcium balance. Its deficiency causes severe bone disease (osteomalacia) and hypocalcemia in mice.
Area of Science:
- Nephrology
- Endocrinology
- Bone Biology
Background:
- Megalin is an endocytic receptor in kidney proximal tubules.
- Megalin is essential for converting 25-OH vitamin D3 to 1,25-(OH)2 vitamin D3.
- Conventional megalin knockout mice are not viable for studying calcium and bone metabolism.
Purpose of the Study:
- To investigate the role of megalin in kidney function, calcium homeostasis, and bone metabolism in vivo.
- To overcome the limitations of previous knockout models.
Main Methods:
- Generated a conditional megalin knockout mouse model with kidney-specific gene inactivation using Cre recombinase.
- Analyzed plasma vitamin D levels, calcium concentrations, and bone parameters (mineral content, osteoid surfaces, mineralization activity).
Main Results:
- Renal-specific megalin deficiency resulted in viable and fertile mice.
- Mice exhibited plasma vitamin D deficiency and hypocalcemia.
- Severe bone disease, including decreased bone mineral content and osteomalacia, was observed.
Conclusions:
- The megalin pathway in the kidney is critical for maintaining systemic calcium homeostasis and bone metabolism.
- Renal megalin is essential for vitamin D activation and preventing hypovitaminosis D-related bone disease.
- This new mouse model is valuable for studying the in vivo functions of megalin.