IKK2 inhibitor alleviates kidney and wasting diseases in a murine model of human AIDS.
Wasting and renal diseases are frequent complications of HIV (human immunodeficiency virus) infection and are associated with accelerated disease progression and increased mortality. Transgenic mice expressing HIV1 under control of the CD4 promoter develop an AIDS-like disease and were used in the present work to study HIV1-induced wasting and kidney pathology. In this study, we reported that disease evolution paralleled increases in serum urea and creatinine levels, indicating an early and progressive deterioration of kidney function; meanwhile the wasting syndrome characterized by up-regulation of the ubiquitine-proteasome pathway and increased level of serum 3-methyl-histidine levels occurred at later stages just prior to death. Further examination of kidney and muscle pathologies revealed a progressive accumulation of CD45(+) cells, first affecting the kidneys. In addition, the onset of disease is accompanied by elevated levels of circulating "regulated on activation, normal and secreted T cell expressed and secreted" (RANTES). These results prompted us to assess the effects of AS602868, a specific small molecule inhibitor of IkappaB kinase 2 (IKK2) on disease progression. Inhibition of the NF-kappaB pathway indeed resulted in increased lifespan, kidney and lean body mass preservation. These beneficial results were associated with a reduction of CD45(+) cells infiltrating the kidneys, amelioration of the renal architecture, and reduced level of circulating RANTES. Together our data provide evidence that IKK2 inhibitors have therapeutic relevance in the treatment of HIV1-associated disorders.
Heckmann
Angélique
A
Serono Pharmaceutical Research Institute, Plan-les-Ouates, Switzerland.
Waltzinger
Caroline
C
Jolicoeur
Paul
P
Dreano
Michel
M
Kosco-Vilbois
Marie H
MH
Sagot
Yves
Y
D000163:Acquired Immunodeficiency Syndrome / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000097:blood; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D019247:HIV Wasting Syndrome / Q000188:drug therapy* / Q000209:etiology; D015497:HIV-1; D006801:Humans; D051550:I-kappa B Kinase; D007674:Kidney Diseases / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014508:Urea / Q000097:blood
D018946:Chemokine CCL5; D004791:Enzyme Inhibitors; D014508:Urea; D003404:Creatinine; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D017493:Leukocyte Common Antigens