Adding a statin to a combination of ACE inhibitor and ARB normalizes proteinuria in experimental diabetes, which translates into full renoprotection.
The capacity of renin-angiotensin system (RAS) inhibitors to delay progression of diabetic nephropathy depends on the time at which therapy is started. A multimodal intervention is required to afford renoprotection in overt diabetic nephropathy. Here we assessed the effects of maximal RAS inhibition by angiotensin-converting enzyme (ACE) inhibitor plus angiotensin II type 1 receptor blocker (ARB) in combination with statin in rats with overt diabetic nephropathy. Uninephrectomized rats made diabetic by streptozotocin were orally treated from 4 (when proteinuria and renal lesions had developed) to 8 mo with vehicle, lisinopril plus candesartan, lisinopril plus candesartan plus rosuvastatin, or rosuvastatin alone. Systolic blood pressure increased in diabetic rats and was significantly lowered by combined therapies. Dual RAS blockade significantly reduced proteinuria compared with vehicle. Addition of statin further lowered proteinuria to control levels. Glomerulosclerosis was ameliorated by RAS inhibitors or statin, and regression was achieved by the addition of statin. Loss of podocytes of diabetic rats was limited by ACE inhibitor plus ARB while normalized by the three drugs. Defective nephrin expression of diabetes was increased by dual RAS blockade or statin and restored by the triple therapy. Tubular damage, interstitial inflammation, and expression of the fibrotic markers transforming growth factor (TGF)-β1 and phosphorylated Smad 2/3 in tubuli were significantly reduced by the triple regimen. These data suggest a strategy to target proteinuria to try to achieve regression of renal disease in diabetic patients who do not fully benefit from RAS inhibition alone.
Zoja
Carla
C
Mario Negri Institute for Pharmacological Research, Centro Anna Maria Astori, Science and Technology Park Km Rosso, Via Stezzano, 87, 24126 Bergamo, Italy. carlamaria.zoja@marionegri.it
Corna
Daniela
D
Gagliardini
Elena
E
Conti
Sara
S
Arnaboldi
Lorenzo
L
Benigni
Ariela
A
Remuzzi
Giuseppe
G
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D002788:Cholesterol Esters / Q000097:blood; D003928:Diabetic Nephropathies / Q000517:prevention & control* / Q000652:urine; D005355:Fibrosis; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D007678:Kidney Glomerulus / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D009395:Nephritis, Interstitial / Q000473:pathology; D050199:Podocytes / Q000473:pathology; D011507:Proteinuria / Q000188:drug therapy* / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D002788:Cholesterol Esters; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; C113267:nephrin; D002784:Cholesterol