Ericsson, A;
Tonelius, P;
Lal, M;
Sabirsh, A;
Böttcher, G;
William-Olsson, L;
Strömstedt, M;
... Unwin, R; + view all
(2017)
The effects of dual PPARα/γ agonism compared with ACE inhibition in the BTBRob/ob mouse model of diabetes and diabetic nephropathy.
Physiological Reports
, 5
, Article e13186. 10.14814/phy2.13186.
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Unwin_The effects of dual PPARα%2Fγ agonism compared with ACE inhibition in the BTBRob%2Fob mouse model of diabetes and diabetic nephropathy.pdf - Published Version Download (3MB) | Preview |
Abstract
The leptin-deficient BTBRob/ob mouse develops progressive albuminuria and morphological lesions similar to human diabetic nephropathy (DN), although whether glomerular hyperfiltration, a recognized feature of early DN that may contribute to renal injury, also occurs in this model is not known. Leptin replacement has been shown to reverse the signs of renal injury in this model, but in contrast, the expected renoprotection by angiotensin-converting enzyme (ACE) inhibition in BTBRob/ob mice seems to be limited. Therefore, to investigate the potential renal benefits of improved metabolic control in this model, we studied the effect of treatment with the dual peroxisome proliferator-activated receptor (PPAR) α/γ agonist AZD6610 and compared it with the ACE inhibitor enalapril. AZD6610 lowered plasma glucose and triglyceride concentrations and increased liver size, but had no significant effect in reducing albuminuria, whereas enalapril did have an effect. Nephrin and WT1 mRNA expression decreased in the kidneys of BTBRob/ob mice, consistent with podocyte injury and loss, but was unaffected by either drug treatment: at the protein level, both nephrin and WT1-positive cells per glomerulus were decreased. Mesangial matrix expansion was reduced in AZD6610-treated mice. GFR, measured by creatinine clearance, was increased in BTBRob/ob mice, but unaffected by either treatment. Unexpectedly, enalapril-treated mice showed intrarenal arteriolar vascular remodeling with concentric thickening of vessel walls. In summary, we found that the BTBRob/ob mouse model shows some similarities to the early changes seen in human DN, but that ACE inhibition or PPARα/γ agonism afforded limited or no kidney protection.
| Type: | Article |
|---|---|
| Title: | The effects of dual PPARα/γ agonism compared with ACE inhibition in the BTBRob/ob mouse model of diabetes and diabetic nephropathy |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.14814/phy2.13186 |
| Publisher version: | http://dx.doi.org/10.14814/phy2.13186 |
| Language: | English |
| Additional information: | ª 2017 AstraZeneca R&D Gothenburg. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited |
| Keywords: | BTBRob/ob mouse, angiotensin‐converting enzyme, diabetic kidney disease, peroxisome proliferator‐activated receptor |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1550362 |
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