ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

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

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Eby, Bonnie, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Pantalia, Meghan M., Columbia University, New York, New York, United States
  • Barron, Lindsay J., University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Lau, Alexander, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Atkins, Richard Matthew, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma, United States
  • Khan, Usman A., University of Oklahoma College of Medicine, Oklahoma City, Oklahoma, United States
  • Tsiokas, Leonidas, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Lau, Kai, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
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