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Title: | Combined inhibition of CCR2 and ACE provides added protection against progression of diabetic nephropathy in Nos3-deficient mice. | Authors: | Pullen N.;Schlerman F.J.;Tesch G.H.;Jesson M.I.;Nikolic-Paterson D.J. | Monash Health Department(s): | Nephrology | Institution: | (Tesch, Nikolic-Paterson) Department of Nephrology, Monash Medical Centre, Clayton, VIC, Australia (Tesch, Nikolic-Paterson) Monash University Centre for Inflammatory Diseases, Clayton, VIC, Australia (Pullen, Jesson, Schlerman) Pfizer Global Research and Development, Cambridge, MA, United States | Issue Date: | 25-Mar-2020 | Copyright year: | 2019 | Publisher: | American Physiological Society | Place of publication: | United States | Publication information: | American Journal of Physiology - Renal Physiology. 317 (6) (pp F1439-F1449), 2019. Date of Publication: 2019. | Journal: | American Journal of Physiology - Renal Physiology | Abstract: | Macrophage-mediated renal injury promotes the development of diabetic nephropathy. Blockade of chemokine (C-C motif) receptor 2 (CCR2) inhibits kidney macrophage accumulation and early glomerular damage in diabetic animals. This study tested early and late interventions with a CCR2 antagonist (CCR2A) in a model of progressive diabetic glomerulosclerosis and determined whether CCR2A provides added benefit over conventional treatment with an angiotensin-converting enzyme inhibitor (ACEi). Diabetes was induced in hypertensive endothelial nitric oxide synthase (Nos3)-deficient mice by administration of five low-dose streptozotocin (STZ) injections daily. Groups of diabetic Nos3- /- mice received a CCR2A (30 mg.kg- 1.day- 1 PF-04634817 in chow) as an early intervention (weeks 2-15 after STZ). The late intervention (weeks 8-15 after STZ) involved PF-04634817 alone, ACEi (captopril in water 10 mg.kg- 1. day- 1) alone, or combined ACEi + CCR2A. Control diabetic and nondiabetic Nos3- /- mice received normal chow and water. Early intervention with a CCR2A inhibited kidney inflammation and glomerulosclerosis, albuminuria, podocyte loss, and renal function impairment but not hypertension in diabetic Nos3- /- mice. Late intervention with a CCR2A also inhibited kidney inflammation, glomerulosclerosis, and renal dysfunction but did not affect albuminuria. ACEi alone suppressed hypertension and albuminuria and partially reduced podocyte loss and glomerulosclerosis but did not affect renal dysfunction. Compared with ACEi alone, the combined late intervention with ACEi + CCR2A provided better protection against kidney damage (inflammation, glomerulosclerosis, and renal function impairment) but not albuminuria. In conclusion, this study demonstrates that combining CCR2A and ACEi provides broader and superior renal protection than ACEi alone in a model of established diabetic glomerulosclerosis with hypertension.Copyright © 2019 the American Physiological Society | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1152/ajprenal.00340.2019 | PubMed URL: | 31566438 [http://www.ncbi.nlm.nih.gov/pubmed/?term=31566438] | ISSN: | 0363-6127 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/35302 | Type: | Article | Subjects: | drug potency drug potentiation early intervention glomerulosclerosis glucose blood level hemoglobin blood level hypertension IC50 kidney function kidney injury monocyte nephritis podocyte streptozotocin-induced diabetic nephropathy/co streptozotocin-induced diabetic nephropathy systolic blood pressure albumin captopril CD68 antigen chemokine receptor CCR2 antagonist cystatin C endothelial nitric oxide synthase glucose hemoglobin A1c messenger RNA protective agent tumor necrosis factor pf 04634817 renal protection albuminuria |
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