Angiotensin II provokes podocyte injury in murine model of HIV-associated nephropathy.
Conditional transgenic mice that express one of the human immunodeficiency virus (HIV)-1 accessory genes, vpr, selectively in podocytes using a podocin promoter and a tetracycline-inducible system develop renal injuries similar to those of patients with HIV-associated nephropathy (HIVAN). We have shown that a heminephrectomy accelerates podocyte injury, which is alleviated by angiotensin II (ANG II) type 1 receptor blocker (ARB). The current study further explores the role of ANG II in the genesis of HIVAN in this murine model. With ANG II infusion, heavy proteinuria was observed at 1 wk after the initiation of doxycycline administration to induce vpr expression in podocytes. Severe morphological and phenotypical changes in the podocytes were observed at 2 wk, together with extensive glomerulosclerosis. Norepinephrine infusion, instead of ANG II, increased the systemic blood pressure to the same level as that achieved using ANG II. However, albuminuria and glomerular injury were modest in norepinephrine-infused mice. Treatment with an ARB, olmesartan, almost completely inhibited glomerular injury. In contrast, lowering the blood pressure with a vasodilator, hydralazine, partially decreased albuminuria but did not produce any histological changes. ANG II infusion alone without doxycycline resulted in a lower level of albuminuria and minimal histological changes. These data demonstrate that excessive ANG II accelerates vpr-induced podocyte injury in a mouse model of HIVAN.
Ideura
Hiroshi
H
Department of Medicine and Clinical Science, Gunma University Graduste School of Medicine, Maebashi, Gunma, Japan.
Hiromura
Keiju
K
Hiramatsu
Noriyuki
N
Shigehara
Tetsuya
T
Takeuchi
Shigeru
S
Tomioka
Mai
M
Sakairi
Toru
T
Yamashita
Shin
S
Maeshima
Akito
A
Kaneko
Yoriaki
Y
Kuroiwa
Takashi
T
Kopp
Jeffrey B
JB
Nojima
Yoshihisa
Y
D016263:AIDS-Associated Nephropathy / Q000378:metabolism / Q000473:pathology*; D000804:Angiotensin II / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D016336:Gene Products, vpr / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009638:Norepinephrine / Q000494:pharmacology; D010641:Phenotype; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000502:physiology
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D016336:Gene Products, vpr; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D009638:Norepinephrine