Early Treatment With Olmesartan Prevents Juxtamedullary Glomerular Podocyte Injury and the Onset of Microalbuminuria in Type 2 Diabetic Rats

• Published in: American journal of hypertension Vol. 25; no. 5; pp. 604 - 611
• Main Authors: Sofue, Tadashi, Kiyomoto, Hideyasu, Kobori, Hiroyuki, Urushihara, Maki, Nishijima, Yoko, Kaifu, Kumiko, Hara, Taiga, Matsumoto, Sachiko, Ichimura, Atsuhiko, Ohsaki, Hiroyuki, Hitomi, Hirofumi, Kawachi, Hiroshi, Hayden, Melvin R., Whaley-Connell, Adam, Sowers, James R., Ito, Sadayoshi, Kohno, Masakazu, Nishiyama, Akira
• Format: Journal Article
• Language: English
• Published: Basingstoke Oxford University Press 01.05.2012; Nature Publishing Group
• Subjects: Albuminuria - etiology; Albuminuria - metabolism; Albuminuria - prevention & control; Angiotensin II Type 1 Receptor Blockers - therapeutic use; Animals; Antihypertensive Agents - therapeutic use; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood Glucose - metabolism; Blood Pressure - physiology; Body Weight - physiology; Cardiology. Vascular system; Diabetes Mellitus, Type 2 - complications; Disease Models, Animal; Experimental diseases; Hydralazine - therapeutic use; Hydrochlorothiazide - therapeutic use; Imidazoles - therapeutic use; Juxtaglomerular Apparatus - injuries; Juxtaglomerular Apparatus - metabolism; Kidney; Male; Medical sciences; Membrane Proteins - metabolism; Podocytes; Rats; Rats, Inbred OLETF; Reserpine - therapeutic use; Tetrazoles - therapeutic use; blood pressure; microalbuminuria; olmesartan; type 2 diabetes mellitus; angiotensin II receptor blockers (ARBs); hypertension; juxtamedullary glomeruli; Endocrinopathy; Type 2 diabetes; Imidazole derivatives; Tetrazole derivatives; Rat; Peptide hormone; Cardiovascular disease; Octapeptide; Arterial pressure; Olmesartan; Blood pressure; Angiotensin II; Microalbuminuria; Hypertension; Urinary system disease; Rodentia; Albumin; Metabolic diseases; Vertebrata; Mammalia; Treatment; Biphenyl derivatives; Animal; Antihypertensive agent; Sartan derivatives; Angiotensin antagonist; angiotensin II receptorblockers (ARBs); Proteinuria
• ISSN: 0895-7061; 1941-7225; 1879-1905
• DOI: 10.1038/ajh.2012.1

Background Studies were performed to determine if early treatment with an angiotensin II (Ang II) receptor blocker (ARB), olmesartan, prevents the onset of microalbuminuria by attenuating glomerular podocyte injury in Otsuka Long-Evans Tokushima Fatty (OLETF) rats with type 2 diabetes mellitus. Methods OLETF rats were treated with either a vehicle, olmesartan (10 mg/kg/day) or a combination of nonspecific vasodilators (hydralazine 15 mg/kg/day, hydrochlorothiazide 6 mg/kg/day, and reserpine 0.3 mg/kg/day; HHR) from the age of 7-25 weeks. Results OLETF rats were hypertensive and had microalbuminuria from 9 weeks of age. At 15 weeks, OLETF rats had higher Ang II levels in the kidney, larger glomerular desmin-staining areas (an index of podocyte injury), and lower gene expression of nephrin in juxtamedullary glomeruli, than nondiabetic Long-Evans Tokushima Otsuka (LETO) rats. At 25 weeks, OLETF rats showed overt albuminuria, and higher levels of Ang II in the kidney and larger glomerular desmin-staining areas in superficial and juxtamedullary glomeruli compared to LETO rats. Reductions in mRNA levels of nephrin were also observed in superficial and juxtamedullary glomeruli. Although olmesartan did not affect glucose metabolism, it decreased blood pressure and prevented the renal changes in OLETF rats. HHR treatment also reduced blood pressure, but did not affect the renal parameters. Conclusions This study demonstrated that podocyte injury occurs in juxtamedullary glomeruli prior to superficial glomeruli in type 2 diabetic rats with microalbuminuria. Early treatment with an ARB may prevent the onset of albuminuria through its protective effects on juxtamedullary glomerular podocytes.