The effects of dual PPAR/ agonism compared with ACE inhibition in the BTBRob/ob mouse model of diabetes and diabetic nephropathy.

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) / 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 PPAR/ agonism afforded limited or no kidney protection.