Sex-specific effects of metformin and liraglutide on renal pathology and expression of connexin 45 and pannexin 1 following long-term high-fat high-sugar diet.

The comparative effects of the two commonly used antidiabetic drugs metformin and liraglutide on renal pathology and expression of connexin 45 (Cx45) and pannexin 1 (Panx1) in adult obese rats fed high-fat high-sugar diet (HFHSD) were studied. Considering recent data on the profound influence of sex on metformin and liraglutide effects, we compared the effects of both drugs between male and female animals. 44-week-old Sprague-Dawley rats were separated into 4 groups that were fed: standard diet, HFHSD, HFHSD treated with metformin (s.c., 50 mg/kg/day) and HFHSD treated with liraglutide (s.c., 0.3 mg/kg/day). Treatment with metformin or liraglutide lasted for 14 weeks. Histology and immunohistochemistry were performed to quantify renal pathological changes and Cx45 and Panx1 expression. HFHSD caused thickening of the Bowman's capsule (BC). Both metformin and liraglutide failed to ameliorate the BC thickening; metformin even worsened it. Effects on the tubulointerstitial fibrosis score, BC thickness and Cx45 and Panx1 expression were sex-dependent. We found a 50% increase in mitochondria in proximal tubules of metformin- and liraglutide-treated HFHSD-fed rats, but these effects were not dependent on the sex. This is a first study showing that the effects of metformin and liraglutide on kidney pathology in rats fed HFHSD are mostly sex-dependent and that these effects are not necessarily beneficial. Both drugs changed the Cx45 and Panx 1 expression; hence their effects could be related to amelioration of disruptions in intercellular communication.

Sigma-1 Receptor Expression in DRG Neurons During a Carrageenan-Provoked Inflammation.

Sigma 1 receptor (σ1R) is a non-opioid receptor that modulates pain perception and is strongly expressed in dorsal root ganglion (DRG) neurons. We studied the changes in the expression of σ1R in different sub-populations of DRG neurons during the first 48 hr in a carrageenan-induced inflammation rat model, with σ1R being a possible base for the development of neuropathic pain after inflammation. Twenty Sprague Dawley rats were divided into five groups (N = 4 in each group): the control (C) group was sacrificed immediately; all other animals received an intraplantar injection of 0.1 mL 2% carrageenan and were sacrificed in 6, 12, 24 or 48 hr after the injection and DRGs were collected and processed for immunohistochemistry. σ1R fluorescence intensity decreased slightly but significantly in up to 24 hr post-carrageenan injection in all sub-populations of DRG neurons (ib4+; ib4- medium, ib4- large and ib4- in total; P < 0.05 - P < 0.001), with the exception of the ib4- small neurons (<25 µm; P > 0.05). This decrement was followed by a subsequent increase in σ1R fluorescence intensity 48 hr after the plantar carrageenan injection (P < 0.05 - P < 0.0001). The same trend was also observed in the CGRP+ population of the DRG neurons, in the total population as well as in the CGRP+ small (<25 µm) and larger CGRP (>25 µm) sub-populations (P < 0.05 - P < 0.001). The presented results may contribute to further understanding of role of σ1R in the development of peripheral sensitization during inflammation. They may also be valuable for the therapeutic application of σ1R antagonists, particularly in the adjustment of the antagonist's dosage in a particular time window. Anat Rec, 302:1620-1627, 2019. © 2019 American Association for Anatomy.