Hypocalcemia and osteopathy in mice with kidney‐specific megalin gene defect

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.

Cellular uptake of steroid carrier proteins—Mechanisms and implications

“…Subsequent studies confirmed the relevance of megalin as a renal retrieval pathway for carrier-bound lipophilic vitamins and hormones essential to prevent uncontrolled urinary loss of these important metabolites (Christensen and Birn, 2001;Muller et al, 2003;Verroust et al, 2002).…”

“…Absence of this DBP receptor pathway in megalin -/-mice results in an inability to retrieve 25-OH vitamin D 3 /DBP complexes from the primary urine and in aberrant excretion of the metabolite. As a consequence of urinary loss of the steroid, plasma levels of 25-OH vitamin D 3 and 1,25-(OH) 2 vitamin D 3 are decreased by more than 70%, resulting in plasma vitamin D deficiency and in bone calcification defects (Hilpert et al, 2002;Leheste et al, 2003;Nykjaer et al, 1999).…”

Localization, mechanism and reduction of renal retention of technetium‐99m labeled epidermal growth factor receptor‐specific nanobody in mice

“…Cells were grown at 378C in a humidified air incubator equilibrated with 5% CO 2 . Female megalin-deficient and megalinexpressing mice were developed in the laboratory of Professor Thomas Willnow (21,22); they were bred and PCR screened in the laboratory of Professor Otto Boerman. Healthy male (ICR/CD1) mice were purchased from Harlan (Horst, The Netherlands).…”

Molecular Mechanisms of Primary Hypercalciuria

“…The urinary loss of vitamin D results in growth retardation and excessive osteoblastic and osteoclastic activity (89). A kidney-targeted megalin knockout is viable; these animals have hypocalcemia and osteomalacia (91). With loss of CLC-5, the amount of megalin in the proximal tubule was reduced in Ϫ/y animals relative to ϩ/y (87).…”