Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy
kidney; disease; Urology & Nephrology; mellitus; rats; progression; nephropathy; advanced glycation end product inhibition diabetic; albuminuria; aminoguanidine; diabetic retinopathy; hydralazine; pimagedine; protein glycation
Background/Aims: Pimagedine inhibits the formation of advanced glycation end products and slows the progression of diabetic complications in experimental models. This study was undertaken to determine if pimagedine ameliorates nephropathy in type 1 ( insulin-dependent) diabetes mellitus. Methods: This was a randomized, double-masked, placebo-controlled study performed in 690 patients with type 1 diabetes mellitus, nephropathy, and retinopathy. The patients received twice daily dosing with placebo, pimagedine 150 mg, or pimagedine 300 mg for 2 - 4 years. The primary end point was the time to doubling of serum creatinine; the secondary end points included evaluations of proteinuria, kidney function, and retinopathy. Results: Serum creatinine doubled in 26% (61/236) of the placebo-treated patients and in 20% (91/454) of those who received pimagedine ( p = 0.099). The estimated glomerular filtration rate decreased more slowly in the pimagedine-treated patients with a 36-month decrease from baseline of 6.26 ml/min/ 1.73 m(2) as compared with 9.80 ml/ min/1.73 m(2) in the placebo-treated patients ( p = 0.05), and pimagedine reduced the 24-hour total urinary proteinuria. ( The mean reduction from baseline at month 36 was 732 mg/24 h at the low dose and 329 mg/24 h at the high dose as compared with 35 mg/24 h in the placebo group; p less than or equal to 0.001.) Fewer pimagedine-treated patients with baseline and end point evaluations (31/324; 10%) as compared with those receiving placebo (16%; 28/179) experienced a three-step or greater progression of the retinopathy ( Early Treatment of Diabetic Retinopathy Study) score ( p = 0.030). Three patients receiving high-dose pimagedine but none receiving low-dose treatment developed glomerulonephritis. Conclusions: While this study did not demonstrate a statistically significant beneficial effect of pimagedine on the progression of overt nephropathy resulting from type 1 diabetes, it is noteworthy in providing the first clinical proof of the concept that inhibiting advanced glycation end product formation can result in a clinically important attenuation of the serious complications of type 1 diabetes mellitus. Copyright (C) 2004 S. Karger AG, Basel.
Bolton W K; Cattran D C; Williams M E; Adler S G; Appel G B; Cartwright K; Foiles P G; Freedman B I; Raskin P; Ratner R E; Spinowitz B S; Whittier F C; Wuerth J P; Grp Action I Investigator
American Journal of Nephrology
2004
2004
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1159/000075627" target="_blank" rel="noreferrer noopener">10.1159/000075627</a>
The role of TRPV4 channels in ocular function and pathologies.
Glaucoma; TRPV4; Angiogenesis; Retina; Calcium channel; Cornea; Diabetic retinopathy; Lens; Osmolarity
Transient potential receptor vanilloid 4 (TRPV4) is an ion channel responsible for sensing osmotic and mechanical signals, which in turn regulates calcium signaling across cell membranes. TRPV4 is widely expressed throughout the body, and plays an important role in normal physiological function, as well as different pathologies, however, its role in the eye is not well known. In the eye, TRPV4 is expressed in various tissues, such as the retina, corneal epithelium, ciliary body, and the lens. In this review, we provide an overview on TRPV4 structure, activation, mutations, and summarize the current knowledge of TRPV4 function and signaling mechanisms in various locations throughout the eye, as well as its role in ocular diseases, such as glaucoma and diabetic retinopathy. Based on the available data, we highlight the therapeutic potential of TRPV4 as well as the shortcomings of current research. Finally, we provide future perspectives on the implications of targeting TRPV4 to treat various ocular pathologies. (Copyright © 2020 Elsevier Ltd. All rights reserved.)
Guarino BD;Paruchuri S;Thodeti CK
Experimental Eye Research
2020
2020-09-29
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1016/j.exer.2020.108257" target="_blank" rel="noreferrer noopener">10.1016/j.exer.2020.108257</a>