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TRPC6 deficiency or feeding a high fat diet impairs ventilatory responses to hypercapnia
Author(s) -
Moak Sydney P.,
Wang Zhen,
da Silva Alexandre A.,
Dai Xuemei,
Hall John E.,
do Carmo Jussara M.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.01980
Subject(s) - hypercapnia , trpc , endocrinology , medicine , plethysmograph , tidal volume , trpc6 , weaning , chemistry , respiratory system , biology , transient receptor potential channel , receptor
Transient receptor potential cation channel C (TRPC) is essential for hypoxic pulmonary vasoconstriction response and alveolar gas exchange. We previously showed that whole body TRCP6 deficient (TRPC6 KO) mice are obese and resistant to the anorexic effects of leptin, a hormone that modulates ventilatory control. In the present study we investigated ventilatory responses to hypercapnia (7% CO 2 ) in male and female 22‐week‐old TRPC6 KO and B6/129 control mice fed normal or high fat diet (HFD) since weaning (n=5 per group/sex/diet). Pulmonary ventilation (V E ), tidal volume (V T ) and respiratory frequency (F R ) were measured using the plethysmography method. TRPC6 KO mice were heavier than control mice when fed normal diet (46.2±1.9 vs. 36.6±2.2 g in males and 34.0±1.4 vs. 26.9±1.3 g in females). However, when fed a HFD, male and female TRPC6 KO and B6/129 mice had similar body weight (43.6±0.4 vs. 47.5±1.4 g and 40.1±0.6 vs. 40.7±2.5 g, respectively). Compared to B6/129 controls male and female TRPC6 KO mice fed normal diet had similar V E (1817± 233 vs. 2139±135 and 2146± 404 vs. 2943±421 ml/min/kg) and V T (10.9±0.6 vs. 9.9±0.6 and 17.0±3.4 vs. 14.6±0.8 ml/kg), but lower F R (130±9 vs. 217±14 and 127±5 vs. 201±26 breaths/min) at room air. During hypercapnia, only male TRPC6 KO mice exhibited lower V E (3631± 493 vs. 6003±698 ml/min/kg), which was due to lower F R (235 ±16 vs. 305±19 breaths/min) and V T (15.3±1.0 vs. 19.5±1.4 ml/kg) responses to 7% CO 2 . Although female TRPC6 KO mice also showed lower F R to hypercapnia compared to B6/129 controls (242±6 vs. 313±22 breaths/min) they exhibited higher V T (28.4±3.0 vs. 25.8±2.0 ml/kg), thus resulting in similarly increased V E (6914±847 vs. 8119±956 ml/min/kg). Male and female B6/129 mice fed a HFD had significantly reduced V E responses to 7% CO 2 (4020± 332 vs. 6003±698 and 5140± 194 vs. 8119±956 ml/min/kg, respectively) that were mainly caused by reduced V T (14.4±1.3 vs. 19.5±1.4 and 18.8±0.6 vs. 25.8±2.0 ml/kg). No further reduction in in ventilatory responses to hypercapnia were observed in male or female TPRC6 KO mice fed a HFD. These results suggest that TRPC6 plays an important role in ventilatory responses to hypercapnia, albeit more profound in males than females, and that HFD significantly reduces ventilatory responses to hypercapnia in both male and female control mice, but not in TRPC6 KO mice. The mechanisms involved in the reduced ventilatory responses are still unclear but may involve reduced sensitivity to leptin evoked by HFD or TRPC6 deficiency. Support or Funding Information NIDDK 1RO1121411, NHLBI‐PO1HL51971, NIGMS P20GM104357 and U54GM115428