Kidney Week

Abstract: TH-PO894

Haploid Deletion of TRPC1 Gene Produces Hypercalcemia, Anemia, Diabetes, and Renal Failure, as Diploid Deletion Causes Obesity, Metabolic Syndrome, Hyperparathyroidism, Liver Steatosis, and Larger Bone Mass

Session Information

• Diabetic Kidney Disease: Basic - I
  October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Eby, Bonnie, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States

Bonnie Eby,

• Pantalia, Meghan M., Columbia University, New York, New York, United States

Meghan M. Pantalia,

• Barron, Lindsay J., University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States

Lindsay J. Barron,

• Lau, Alexander, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States

Alexander Lau,

• Atkins, Richard Matthew, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma, United States

Richard Matthew Atkins,

• Khan, Usman A., University of Oklahoma College of Medicine, Oklahoma City, Oklahoma, United States

Usman A. Khan,

• Tsiokas, Leonidas, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States

Leonidas Tsiokas,

• Lau, Kai, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States

Kai Lau,

Background

The gene encoding the canonical transient recpetor potential 1 channel (TRPC1) is ubiquitously expressed. It is known to be involved in signal transduction by changing intracellular Ca, cytokine & hormone secretion, cell proliferation & differentiation. Gene deletion is now known to produce a myriad of abnromal but nonlethal phenotypes, including hypercalcemia, anemia, diabetes, renal failure, obesity, metabolic syndrome, hyperparathyroidism, hepatic steatosis & increased bone mass. We tested the hypothesis of relative gene dosge in these phenotypes by studying ♂ littermates of all 3 genotypea born to only +/- breeders.

Methods

Standard metabolic studies, glucose tolerance tests, & routine lab chemistry were done from age 1 to 22 m. Mouse ELISA were used to measure insulin, PTH, adipokines & FGF-23. Creatinine (Cr) was measured by HPLC & glomerular filtration rate (GFR) by inulin or Cr clearance .

Results

In +/- mice, like the null, we found fasting hyperglycemia at 3 m, diabetes at 6 m, hypercalcemia at 7-12 m, anemia at 11 m, & reduced GFR of 40% at 16 m. However, only in null mice could we document the following phenotypes: hyperphagia, excessive weight gain, obesity, hypertriglyceridemia (all at 2-4 m), reduced serum FGF 23 at 3-5 m, metabolic syndrome at 6 m, increased serum leptin & reduced adiponectin at 7 m, hepatic steatosis at 12 mon, hyperparathyroidism despite hypercalcemia & hypocalciuria [like the human familial hypocalciuric hypercalcemia (FHH)] at 12 m, & increased bone mass at 19-22 m. Liver triglyceride content was elevated only in null mice. If haploid deletion replicates the phenotypes of diploid deletion, the degree of abnormalities was uniformly ccomparable.

Conclusion

We conclude: 1. Since haploid deficiency of TRPC1 gene produces anemia, diabetes, hypercalcemia & renal failure, the usual normal phenotypes would require both wild type alleles. 2. Since diplid deficiency is needed to produce hyperphagia, obesity, metabolic syndrome, FHH, hepatic steatosis & increased bone mass, the corresponding normal phenotypes can be maintained by 1 wild type allele. 3. Additional insights on the pathobiology will depend on studies in tissue-specific TRPC1 gene deletion.

Funding

• NIDDK Support