Local delivery of angiotensin II receptor blockers into the kidney passively attenuates inflammatory reactions during the early phases of streptozotocin-induced diabetic nephropathy through inhibition of calpain activity.
OBJECTIVE
Inhibition of the renin-angiotensin-aldosterone system plays a pivotal role in the prevention and treatment of diabetic nephropathy. Angiotensin II receptor blockers (ARB) exert a renoprotective effect and attenuate the progression of diabetic nephropathy. However, the underlying cellular and molecular mechanisms in the kidney remain to be elucidated. The present study was undertaken to focus on the effect of local angiotensin II type 1 receptor blockade on the inflammatory reaction during the early stages of diabetic nephropathy.


RESULTS
Local ARB treatment significantly reduced urinary protein excretion and serum blood urea nitrogen levels in streptozotocin-induced diabetic nephropathy. In addition, this treatment attenuated monocyte/macrophage infiltration into the glomeruli and the enhanced glomerular expression of endothelial nitric oxide synthase at both the mRNA and protein levels. Immunohistochemical study revealed activation of nuclear factor (NF)-kappaB, as shown by an increase in the expression of the p65 subunit of NF-kappaB and its translocation from the cytoplasm to the nucleus in both tubular epithelial and glomerular cells of the diabetic kidney. Local ARB treatment induced an apparent reduction in p65 nuclear localization and intensity of staining. To search for a common and fundamental candidate that influences endothelial cell function and vascular inflammation, we examined glomerular calpain activity in diabetic rats with or without ARB treatment. Glomerular expression of 145/150-kDa spectrin breakdown products, a specific product of calpain activation, was dramatically increased in diabetic animals while the protein expression reverted to a normal level after ARB treatment.


CONCLUSIONS
Our findings provide a conceptual basis for the development of therapeutic strategies aiming at local inhibition of the renin-angiotensin system to prevent the progression of diabetic nephropathy.
Kamal
Fadia
F
Department of Cellular Physiology, Institute of Nephrology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
Yanakieva-Georgieva
Nadezhda
N
Piao
Honglan
H
Morioka
Tetsuo
T
Oite
Takashi
T
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D007249:Inflammation / Q000188:drug therapy; D007678:Kidney Glomerulus / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000187:drug effects; D013311:Streptozocin; D013777:Tetrazoles / Q000627:therapeutic use*; D051996:Transcription Factor RelA / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068756:Valsartan
D047228:Angiotensin II Type 1 Receptor Blockers; D016328:NF-kappa B; D013777:Tetrazoles; D051996:Transcription Factor RelA; D013311:Streptozocin; D000068756:Valsartan; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D002154:Calpain; D014633:Valine