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Kidney Week

Abstract: FR-PO385

Renal Failure Induced by Deletion of the Gene Encoding Canonical Transient Receptor Potential 1 (TRPC1) Channels: A Mouse Model of Normotensive CKD

Session Information

  • CKD: Mechanisms - II
    November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Eby, Bonnie, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
  • Pantalia, Meghan M., University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
  • Skaggs, Chris D., University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
  • Barron, Lindsay J., University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
  • Khan, Usman A., University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
  • Lau, Kai, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
Background

TRPC1 plays a key role in cardiac hypertrophy, vascular smooth muscle proliferation & glomerular mesangial cell contractility. It is reduced in diabetes, but exact relationship is unknown. Since TRPC1 deletion produces diabetes & cardiomyopathy, we tested for renal phenotypes in TRPC1 deficiency.

Methods

In age-matched wild types, +/- & null males, from 1 - 20 mon, we measured serial blood glucose, blood & urine creatinine (Cre) by HPLC. Renal ultrasound was done at 7, 11, & 20 mon. Glomerular filtration rate (GFR) was estimated by Cre clearance (C) & confirmed by inulin C. Blood pressure (BP) was measured directly by arterial cannulation.

Results

Despite hyperglycemia from 3 mon on & diabetes at 6 mon, kidney volume at 7 mon (0.38 vs 0.46 cc) & kidney weight (KW) to body (B) W (1.2 vs 1.5 %) were 17% lower in null. From 11- 20 mon, kidney volume (0.4 vs 0.5 cc) stayed 16% lower & KW:BW (1.1 vs 1.5 %) 28% lower. Renal echogenicity was similar at 7 & 11 mon but increased by 37% at 20 mon, sugggesting injury & scarring. Normal at 12 mon, serum Cre (0.1 vs. 0.06 mg%) was elevated at 17 mon. Cre C fell by 42% (0.66 vs. 1.13 ml/min/mouse) & by 50% when factored for BW (1.7 vs. 3.4 ml/min/100g). Renal failure was confirmed by 44 to 48% reduction in GFR (214 vs 384 µl/min per mouse; 603 vs 1,155 µl/min per100 g BW; 362 vs 681 µl/min/ per g KW). There was no hypertension based on systolic BP (in torr) (113 vs. 121), diastolic (77 vs. 86) or mean (89 vs. 98). Urine concentration ability was intact by osmolality after 17 h dehydration. Urine acidification was impaired in null based on urine pH (6.0 vs 5.2). Urine albumin was increased in null (12 vs 7 µg/d or 23 vs 14 µg/mg Cre). Haploid deletion prduced similar renal phenotypes.

Conclusion

1. Both haploid & diploid TRPC1 deletion produces nephropathy based on 50% GFR loss, reduced kidney volume, and increased echogenicity. It offers an excellent model to study non-hypertensive CKD. 2. Though renal failure emerges ~12 mon after diabetes, the small kidney size at the outset & the minimal proteinuria favor hypoplastic over diabetic nephropathy. 4. We propose that the TRPC1 protein is key in normal growth & development for the kidney (as for the heart) & a possibl role in hyperfiltration in response to diabetes.

Funding

  • NIDDK Support