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Increased glomerular filtration rate and impaired contractile function of mesangial cells in TRPC6 knockout mice.

ABSTRACT: The present study was conducted to determine if TRPC6 regulates glomerular filtration rate (GFR) and the contractile function of glomerular mesangial cells (MCs). GFR was assessed in conscious TRPC6 wild type and knockout mice, and in anesthetized rats with and without in vivo knockdown of TRPC6 in kidneys. We found that GFR was significantly greater, and serum creatinine level was significantly lower in TRPC6 deficient mice. Consistently, local knockdown of TRPC6 in kidney using TRPC6 specific shRNA construct significantly attenuated Ang II-induced GFR decline in rats. Furthermore, Ang II-stimulated contraction and Ca2+ entry were significantly suppressed in primary MCs isolated from TRPC6 deficient mice, and the Ca2+ response could be rescued by re-introducing TRPC6. Moreover, inhibition of reverse mode of Na+-Ca2+ exchange by KB-R7943 significantly reduced Ca2+ entry response in TRPC6-expressing, but not in TRPC6-knocked down MCs. Ca2+ entry response was also significantly attenuated in Na+ free solution. Single knockdown of TRPC6 and TRPC1 resulted in a comparable suppression on Ca2+ entry with double knockdown of both. These results suggest that TRPC6 may regulate GFR by modulating MC contractile function through multiple Ca2+ signaling pathways.

SUBMITTER: Li W

PROVIDER: S-EPMC5482875 | biostudies-other | 2017 Jun

REPOSITORIES: biostudies-other

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Increased glomerular filtration rate and impaired contractile function of mesangial cells in TRPC6 knockout mice.

Li Weizu W Ding Yanfeng Y Smedley Crystal C Wang Yanxia Y Chaudhari Sarika S Birnbaumer Lutz L Ma Rong R

Scientific reports 20170623 1

The present study was conducted to determine if TRPC6 regulates glomerular filtration rate (GFR) and the contractile function of glomerular mesangial cells (MCs). GFR was assessed in conscious TRPC6 wild type and knockout mice, and in anesthetized rats with and without in vivo knockdown of TRPC6 in kidneys. We found that GFR was significantly greater, and serum creatinine level was significantly lower in TRPC6 deficient mice. Consistently, local knockdown of TRPC6 in kidney using TRPC6 specific ...[more]

PMID: 28646178

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Project description:PurposeTo assess the accuracy of glomerular filtration rate (GFR) measurements obtained with low-contrast agent dose dynamic contrast material-enhanced magnetic resonance (MR) renography in patients with liver cirrhosis who underwent routine liver MR imaging, with urinary clearance of technetium 99m ((99m)Tc) pentetic acid (DTPA) as the reference standard.Materials and methodsThis HIPAA-compliant study was institutional review board approved. Written informed patient consent was obtained. Twenty patients with cirrhosis (14 men, six women; age range, 41-70 years; mean age, 54.6 years) who were scheduled for routine 1.5-T liver MR examinations to screen for hepatocellular carcinoma during a 6-month period were prospectively included. Five-minute MR renography with a 3-mL dose of gadoteridol was performed instead of a routine test-dose timing examination. The GFR was estimated at MR imaging with use of two kinetic models. In one model, only the signal intensities in the aorta and kidney parenchyma were considered, and in the other, renal cortical and medullary signal intensities were treated separately. The GFR was also calculated by using serum creatinine levels according to the Cockcroft-Gault and modification of diet in renal disease (MDRD) formulas. All patients underwent a (99m)Tc-DTPA urinary clearance examination on the same day to obtain a reference GFR measurement. The accuracies of all MR- and creatinine-based GFR estimations were compared by using Wilcoxon signed rank tests.ResultsThe mean reference GFR, based on (99m)Tc-DTPA clearance, was 74.9 mL/min/1.73 m(2) ± 27.7 (standard deviation) (range, 10.3-120.7 mL/min/1.73 m(2)). With both kinetic models, 95% of MR-based GFRs were within 30% of the reference values, whereas only 40% and 60% of Cockcroft-Gault- and MDRD-based GFRs, respectively, were within this range. MR-based GFR estimates were significantly more accurate than creatinine level-based estimates (P < .001).ConclusionGFR assessment with MR imaging, which outperformed the Cockcroft-Gault and MDRD formulas, adds less than 10 minutes of table time to a clinically indicated liver MR examination without ionizing radiation.Supplemental materialhttp://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.11101338/-/DC1.

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Increased glomerular filtration rate and impaired contractile function of mesangial cells in TRPC6 knockout mice.

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Increased glomerular filtration rate and impaired contractile function of mesangial cells in TRPC6 knockout mice.

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