Effects of combination PPARγ agonist and angiotensin receptor blocker on glomerulosclerosis

Abstract

We previously observed that high-dose angiotensin receptor blocker (ARB) can induce regression of existing glomerulosclerosis. We also found that proliferator-activated recepto-γ (PPARγ) agonist can attenuate glomerulosclerosis in a nondiabetic model of kidney disease, with specific protection of podocytes. We now assessed effects of combination therapy with ARB and pioglitazone on established glomerulosclerosis. Sprague-Dawley male rats underwent 5/6 nephrectomy (5/6 Nx) at week 0 and renal biopsy at week 8. Rats were randomized to groups with equal starting moderate glomerulosclerosis, and treated with ARB, PPARγ agonist (pioglitazone), combination or vehicle from weeks 8 to 12. Body weight, systolic blood pressure (SBP), and urinary protein (UP) were measured at intervals. In rats with established sclerosis, SBP, UP, and GS were equal in all groups at week 8 before treatment by study design. Untreated control rats had hypertension, decreased GFR, and progressive proteinuria and glomerulosclerosis at week 12. Only combination therapy significantly ameliorated hypertension and proteinuria. ARB alone or pioglitazone alone had only numerically lower SBP and UP than vehicle at week 12. Both pioglitazone alone and combination had significantly less decline in GFR than vehicle. Combination-induced regression of glomerulosclerosis in more rats from weeks 8 to 12 than ARB or pioglitazone alone. In parallel, combination treatment reduced plasminogen activator inhibitor-1 expression and macrophage infiltration, and preserved podocytes compared with vehicle. These results were linked to increased AT2 receptor and Mas1 mRNA in the combination group. PPARγ agonists in combination with ARB augment regression of glomerulosclerosis, with downregulation of injurious RAAS components vs PPARγ alone, with increased anti-fibrotic/healing RAAS components, enhanced podocyte preservation, and decreased inflammation and profibrotic mechanisms.

Azilsartan as “Add-On” Treatment with Methotrexate Improves the Disease Activity of Rheumatoid Arthritis

“…Our study revealed that Azil may improve the inhibitory effects of MTX on tissue destruction attributed to the excessive production of damaging inflammatory mediators within the inflamed joint tissues. The results of the present study are consistent with previously reported data, where Azil or other ARBs decreased synthesis of the proinflammatory cytokines by various mechanisms including Ang II type-1 receptor blockade and/or activation of PPAR- γ nuclear receptors [ 27 ]. In our study, Azil enhanced the antirheumatic effect of MTX, manifested as a significantly greater improvement in the clinical and biochemical markers compared to the use of MTX with the placebo formula.…”

Podocyte-Related Mechanisms Underlying Survival Benefit of Long-Term Angiotensin Receptor Blocker

“…Previous studies in human CKD have shown that multipronged therapy, including maximum proteinuria reduction by titrated dual renin-angiotensin-system (RAS) inhibition, amelioration of dyslipidemia with statins, smoking cessation, lowering salt intake, and healthy lifestyle implementation, can regress CKD [ 23 , 33 ]. Similarly, we and others have found that a combination of aldosterone synthase inhibitor and ARB, or a combination of proliferator-activated receptor γ (PPARγ) agonist and ARB, induced more regression of glomerulosclerosis than monotherapy in the 5/6 nephrectomy model [ 34 ]. These additional protective effects were related to less inflammation and more podocyte protection.…”

Azilsartan improves the effects of etanercept in patients with active rheumatoid arthritis: a pilot study

“…Azilsartan or other ARBs that have a pleiotropic function are well-known to hinder certain types of inflammatory processes through inhibiting neutrophil migration, attenuation of the exaggerated immune function or through the PPAR-γ pathway. 38 Moreover, azilsartan effectively attenuates tissue damage and granulation tissue formation in an experimental animal model of non-alcoholic fatty liver disease (NAFLD) 28 and may be suggested as a part of a future therapeutic strategy of chronic inflammatory disorders. Rheumatoid arthritis was a disease of heterogeneous nature, and the use of single disease activity variable for diagnosis and treatment follow up was not considered as a valid or accurate approach.…”