Calcium channel blockers, either amlodipine or mibefradil, ameliorate renal injury in experimental diabetes

• Published in: Kidney international Vol. 66; no. 3; pp. 1090 - 1098
• Main Authors: Ma, Guorong, Allen, Terri J., Cooper, Mark E., Cao, Zemin
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.09.2004; Nature Publishing; Elsevier Limited
• Subjects: albuminuria; Albuminuria - drug therapy; Albuminuria - pathology; amlodipine; Amlodipine - pharmacology; Animals; Azo Compounds; Biological and medical sciences; Blood Pressure - drug effects; Calcium Channel Blockers - pharmacology; collagen I; Collagen Type I - genetics; Coloring Agents; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - pathology; Diabetic Nephropathies - physiopathology; diabetic nephropathy; fibronectin; Fibronectins - genetics; Gene Expression - drug effects; Kidney - metabolism; Kidney - pathology; Kidneys; Male; Medical sciences; mibefradil; Mibefradil - pharmacology; Nephrology. Urinary tract diseases; Organ Size; Rats; Rats, Sprague-Dawley; Urinary system involvement in other diseases. Miscellaneous; mibefradil; albuminuria; fibronectin; diabetic nephropathy; amlodipine; collagen I; Endocrinopathy; Kidney disease; Antianginal agent; Mibefradil; Nephrology; Urinary system disease; Injury; Diabetes mellitus; Glycoprotein; Calcium antagonist; Fibronectin; Urology; Urinary system; Benzimidazole derivatives; Collagen; Amlodipine; Antihypertensive agent; Diabetic nephropathy; Dihydropyridine derivatives
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1111/j.1523-1755.2004.00859.x

Calcium channel blockers, either amlodipine or mibefradil, ameliorate renal injury in experimental diabetes. Diabetic nephropathy is associated with increased albuminuria and accmulation of extracellular matrix proteins within the kidney. Clinical studies have shown some beneficial effects of calcium channel blockers (CCB) on diabetic nephropathy, even though they are generally considered to be less renoprotective than agents that interrupt the renin angiotensin system. However, effects of CCBs on renal injury, and in particular, expression of extracellular matrix proteins in a model of normotensive diabetic nephropathy, are poorly characterized. Experimental diabetes was induced by injection of streptozocin in Sprague-Dawley rats. Amlodipine, a CCB which blocks the L channel, and mibefradil, a CCB blocking the T as well as the L channels, were given to diabetic rats for six months. Albumin excretion rate (AER), pathologic injury, and expression of the extracellular matrix proteins, collagen I, and fibronectin were assessed. Increased AER in diabetic rats (13.2 ×/÷1.3 mg/d, geometric mean ×/÷ tolerance factor) was attenuated by either amlodipine (3.2 ×/÷ 1.4 mg/d) or mibefradil (2.6 ×/÷ 1.4 mg/d). Increased glomerulosclerosis and tubulointerstitial injury in diabetic animals were attenuated by amlodipine and mibefradil. There was increased collagen accmulation in the kidney of diabetic rats as assessed by picro-sirius red staining. Gene expression of both collagen I and fibronectin were also increased in the kidneys from diabetic animals, as assessed by reverse transcription-polymerase chain reaction (RT-PCR). These markers of fibrosis were attenuated by treatment with either amlodipine or mibefradil. Blood pressure in diabetic rats (136 ± 2 mm Hg) was modestly reduced by amlodipine (126 ± 3 mm Hg) but not by mibefradil treatment (134 ± 3 mm Hg). Calcium channel blockers attenuated albuminuria, pathologic injury, and accmulation of extracellular matrix proteins in this normotensive model of diabetic nephropathy. These findings suggest that CCBs may be useful in preventing pathologic injury in the diabetic kidney.