Renal phospholipidosis and impaired magnesium handling in high‐fat‐diet–fed mice

Abstract

Hypomagnesemia (blood Mg2+ concentration <0.7 mM) is a common electrolyte disorder in patients with type 2 diabetes (T2D), but the etiology remains largely unknown. In patients with T2D, reduced blood Mg2+ levels are associated with an increased decline in renal function, independent of glycemic control and hypertension. To study the underlying mechanism of this phenomenon, we investigated the renal effects of hypomagnesemia in high‐fat‐diet (HFD)‐fed mice. In mice fed a low dietary Mg2+, the HFD resulted in severe hypomagnesemia within 4 wk. Renal or intestinal Mg2+ wasting was not observed after 16 wk on the diets. Despite the absence of urinary or fecal Mg2+ loss, the HFD induced a reduction in the mRNA expression transient receptor potential melastatin type 6 in both the kidney and colon. mRNA expression of distal convoluted tubule (DCT)‐specific genes was down‐regulated by the LowMg‐HFD, indicating atrophy of the DCT. The low dietary Mg2+ resulted in severe HFD‐induced proximal tubule phospholipidosis, which was absent in mice on a NormalMg‐HFD. This was accompanied by albuminuria, moderate renal damage, and alterations in renal energy metabolism, including enhanced gluconeo‐genesis and cholesterol synthesis. In conclusion, this study shows that hypomagnesemia is a consequence of diet‐induced obesity and insulin resistance. Moreover, hypomagnesemia induces major structural changes in the diabetic kidney, including proximal tubular phospholipidosis, providing a novel mechanism for the increased renal decline in patients with hypomagnesemic T2D.—Kurstjens, S., Smeets, B., Overmars‐Bos, C., Dijkman, H. B., den Braanker, D. J. W., de Bel, T., Bindels, R. J. M., Tack, C. J. J., Hoenderop, J. G. J., de Baaij, J. H. F. Renal phospholipidosis and impaired magnesium handling in high‐fat‐diet–fed mice. FASEB J. 33, 7192–7201 (2019). http://www.fasebj.org

Low gut microbiota diversity and dietary magnesium intake are associated with the development of PPI‐induced hypomagnesemia

“…phenomenon in different mouse models of hypomagnesemia (42)(43)(44). This might suggest that compensation of Mg 2+ reabsorption in intestine and kidney might have been initiated in the early treatment phase, resulting in an adapted set-point of Mg 2+ balance.…”

mTOR-Activating Mutations in RRAGD Are Causative for Kidney Tubulopathy and Cardiomyopathy

“…Later, two additional patient cohorts were examined: (1) a cohort with isolated tubulopathy and suspected diagnosis of Gitelman syndrome (n558) who had been subjected to WES; and (2) a cohort of patients with dilated cardiomyopathy (n574), in whom mutations in known cardiomyopathy genes had previously been excluded by targeted exome sequencing of 174 cardiovascular genes, including 49 cardiomyopathy genes, as previously described. 17 Cell Lysates and Immunoprecipitation Human embryonic kidney (HEK293T) cells were transfected with Flag-S6K1, RagA, and RagD mutants, as described previously. 15 To determine the response of mechanistic target of rapamycin complex 1 (mTORC1) to amino acid stimulation or starvation under the control of Rag mutants, 2 million HEK293T cells were plated onto a 10-cm dish.…”

Magnesium Picolinate Improves Bone Formation by Regulation of RANK/RANKL/OPG and BMP-2/Runx2 Signaling Pathways in High-Fat Fed Rats

“…Previous studies have shown that HFD and Western diet can reduce BMD levels [ 19 , 33 , 34 , 35 , 36 ]. Feeding with HFD may interfere with intestinal mineral absorption and renal reabsorption [ 22 ], especially Mg and Ca [ 21 , 37 ]. This may have decreased bone Ca, P, Mg, and Zn levels in the HFD rats.…”

“…Moreover, intestinal mineral absorption and mineral homeostasis in kidneys may be interrupted by HFD intake. Then, Ca and Mg metabolisms, which are essential for bone formation, may be disrupted [ 21 , 22 ].…”