title: Angiotensin II-dependent persistent podocyte loss from destabilized glomeruli causes progression of end stage kidney disease.
abstract: Podocyte depletion is a major mechanism driving glomerulosclerosis. Progression is the process by which progressive glomerulosclerosis leads to end stage kidney disease (ESKD). In order to determine mechanisms contributing to persistent podocyte loss, we used a human diphtheria toxin transgenic rat model. After initial diphtheria toxin-induced podocyte injury (over 30% loss in 4 weeks), glomeruli became destabilized, resulting in continued autonomous podocyte loss causing global podocyte depletion (ESKD) by 13 weeks. This was monitored by urine mRNA analysis and by quantitating podocytes in glomeruli. Similar patterns of podocyte depletion were found in the puromycin aminonucleoside and 5/6 nephrectomy rat models of progressive end-stage disease. Angiotensin II blockade (combined enalapril and losartan) restabilized the glomeruli, and prevented continuous podocyte loss and progression to ESKD. Discontinuing angiotensin II blockade resulted in recurrent glomerular destabilization, podocyte loss, and progression to ESKD. Reduction in blood pressure alone did not reduce proteinuria or prevent podocyte loss from destabilized glomeruli. The protective effect of angiotensin II blockade was entirely accounted for by reduced podocyte loss. Thus, an initiating event resulting in a critical degree of podocyte depletion can destabilize glomeruli and initiate a superimposed angiotensin II-dependent podocyte loss process that accelerates progression resulting in eventual global podocyte depletion and ESKD. These events can be monitored noninvasively in real-time through urine mRNA assays.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109-5676, USA.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Fukuda
authors.forename: Larysa T
authors.initials: LT
authors.lastname: Wickman
authors.forename: Madhusudan P
authors.initials: MP
authors.lastname: Venkatareddy
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sato
authors.forename: Mahboob A
authors.initials: MA
authors.lastname: Chowdhury
authors.forename: Su Q
authors.initials: SQ
authors.lastname: Wang
authors.forename: Kerby A
authors.initials: KA
authors.lastname: Shedden
authors.forename: Robert C
authors.initials: RC
authors.lastname: Dysko
authors.forename: Jocelyn E
authors.initials: JE
authors.lastname: Wiggins
authors.forename: Roger C
authors.initials: RC
authors.lastname: Wiggins
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D007676:Kidney Failure, Chronic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic
chemical_list: D000959:Antihypertensive Agents; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D012333:RNA, Messenger; C113267:nephrin; D000804:Angiotensin II