Kidney Week

Abstract: FR-PO506

Ghrelin Enhances Tubular Magnesium Absorption in the Kidneys

Session Information

• Fluid, Electrolyte, Acid-Base Disorders: Basic
  November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid, Electrolytes, and Acid-Base Disorders

• 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

• Wolf, Matthias Tilmann, The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Matthias Tilmann Wolf,

• Nie, Mingzhu, The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Mingzhu Nie,

• Zhang, Jing, The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Jing Zhang,

• Bal, Manjot S., The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Manjot S. Bal,

• Baum, Michel G., The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Michel G. Baum,

Background

In animal models mimicking bariatric procedures, bone disease, decreased serum levels of Ca²⁺, Mg²⁺ and the gastric hormone Ghrelin were described. Ghrelin binds to the growth hormone secretagogue-receptor (GHSR) which is expressed in renal tubules. We tested if Ghrelin modifies tubular calcium or magnesium absorption via the ion channels TRPV5 or TRPM6.

Methods

We expressed GHSR1 with TRPV5 or TRPM6 channel in HEK293 cells and treated them with purified Ghrelin. Whole-cell current density was analyzed by patch-clamp recording. Nephron-specific gene expression of Ghrelin, GHSR, and Trpm6, was determined in microdissected tubules. Tubular localization of GHSR was examined by immunofluorescent (IF) imaging of GHSR-GFP mice. As there is more Ghrelin secreted with fasting, we elucidated the effect of Ghrelin in tubular magnesium homeostasis in GHSR-null mice at baseline and after starvation.

Results

After Ghrelin exposure whole-cell current density did not change for TRPV5 but increased for TRPM6 in a dose-dependent fashion. While a Ghrelin-mimetic also increased TRPM6 current density, addition of a GHSR antagonist inhibited the effect. GHSR signals via protein kinase A (PKA) and applying the PKA inhibitor H89 abrogated TRPM6 stimulation by Ghrelin. In microdissected tubules of wild-type (WT) mice there was abundant Ghrelin and GHSR mRNA in the TAL with 50% lower levels in microdissected DCTs. TRPM6 was highly expressed in the DCT. Unexpectedly, we also detected TRPM6 mRNA in the TAL at 15% expression compared to DCT. IF studies of GHSR-GFP mice confirmed a GFP signal in the TAL but not in the DCT. In 3, 6, and 9 month-old GHSR-null and WT mice, baseline serum magnesium and 24-hour urinary excretion of magnesium was not significantly different. Starved GHSR-null mice, displayed a significantly higher urinary magnesium excretion and lower serum magnesium levels with downregulation of tubular magnesiotropic genes Hnf1b, Cldn-16, Cldn-19, Fxyd-2b, and Parvalbumin.

Conclusion

Ghrelin stimulates TRPM6 via GHSR and Gα_s-PKA signaling in vitro. The physiological significance of this mechanism is unclear given the higher GHSR mRNA abundance in the TAL compared to DCT. Starved GHSR-null mice had increased urinary magnesium excretion and lower serum magnesium levels. This may be mediated by Ghrelin-upregulation of TRPM6 in the TAL and/or upregulation of other magnesiotropic genes.

Funding

• NIDDK Support