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Kidney Week

Abstract: PO0599

Induction of CKD by Gene Deletion of Canonical Transient Receptor Potential 1 (TRPC1) Channels Independent of Hypertension and Nephromegaly Despite Diabetes and Metabolic Syndrome

Session Information

  • CKD Mechanisms - 1
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Anwar, Muhammad Mubeen, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Khan, Usman A., The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Eby, Bonnie, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Lau, Kai, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
Background

TRPC1 gene on chromosome 3q22-24 is in the linkage region for diabetic nephropathy. Despite reduced expression in diabetes, no causal relationship has been shown. Since null mice are obese, hypertriglyceridemic and diabetic with fatty liver, we evaluated potential renal phenotypes, testing the hypothesis of impaired Ca signaling, as we found reduced cell free Ca in bone, renal, and parathyroid cells.

Methods

From 3rd to 22nd mon, metabolic, cardiac & abdominal ultrasound (US) & clearance (Cl) studies were done in age- & sex-matched littermates of TRPC1 +/+, +/-, & -/- mice. Creatinine (Cr) was analyzed by creatininase or HPLC; glomerular filtration rate (GFR) by inulin Cl. Systolic (S) & diastolic (D) BP was measured by arterial (A) cannulation.

Results

Null mice were hyperglycemic from the 3rd mon & developed diabetes from 6 to 22 mon by standard IP glucose tolerance test. Nephromegaly was absent in null mice since kidney volume by US (0.38 vs. 0.46 at 7 mon & 0.4 vs 0.5 cc at 11-20 mon) was 16% smaller & kidney (K) to body (B) weight (W) (1.2 vs.1.5 % at 7 mon & 1.1 vs.1.5 % at 11-20 mon) was lighter by 17-28 %. Chronic injury & scarring were suggested by 37% increase in echogenicity at 20 mon, though normal at 7 or 11 mon. Urine albumin/Cr ratio in null mice rose barely (64-71%). But at 17 mon, CrCl fell by 30% (p<0.01) in null ♀ & by 46% (p<0.01) in null ♂. GFR at 22 mon corroborated stage III CKD as inulin Cl fell by 45-48%, whether expressed per mouse, per g KW, or per 100 g BW. Haploid TRPC1 deletion reduced CrCl by in 40% (p<0.05) at 16 mon vs 44% by diploid deletion (p<0.02). TRPC1 deletion significantly reduced, not raised, mean SBP (113 vs 131 torr), DBP (77 vs 86 torr), & MABP (89 vs 98 torr). Since TRPC1 was implicated in cardiac hypertrophic signaling, smooth muscle proliferation & mesangial cell contraction, we did cardiac US & found 33% reduced cardiac output in -/- mice (14 vs 21 ml/min) & 14% smaller heart mass, corroborated by 20% lower weights measured at 22 mon.

Conclusion

1. TRPC1 deficiency impairs Ca signaling, retards renal & heart development, compromizes hemodynamics and produces hypoplastic nephropathy. 2. Null mice provide an excellent model to study progressive CKD independent of hypertension and heavy proteinuria.

Funding

  • NIDDK Support