AT1 blockade during lactation as a model of chronic nephropathy: mechanisms of renal injury.
Suppression of the renin-angiotensin system during lactation causes irreversible renal structural changes. In this study we investigated 1) the time course and the mechanisms underlying the chronic kidney disease caused by administration of the AT(1) receptor blocker losartan during lactation, and 2) whether this untoward effect can be used to engender a new model of chronic kidney disease. Male Munich-Wistar pups were divided into two groups: C, whose mothers were untreated, and L(Lact), whose mothers received oral losartan (250 mg.kg(-1).day(-1)) during the first 20 days after delivery. At 3 mo of life, both nephron number and the glomerular filtration rate were reduced in L(Lact) rats, whereas glomerular pressure was elevated. Unselective proteinuria and decreased expression of the zonula occludens-1 protein were also observed, along with modest glomerulosclerosis, significant interstitial expansion and inflammation, and wide glomerular volume variation, with a stable subpopulation of exceedingly small glomeruli. In addition, the urine osmolality was persistently lower in L(Lact) rats. At 10 mo of age, L(Lact) rats exhibited systemic hypertension, heavy albuminuria, substantial glomerulosclerosis, severe renal interstitial expansion and inflammation, and creatinine retention. Conclusions are that 1) oral losartan during lactation can be used as a simple and easily reproducible model of chronic kidney disease in adult life, associated with low mortality and no arterial hypertension until advanced stages; and 2) the mechanisms involved in the progression of renal injury in this model include glomerular hypertension, glomerular hypertrophy, podocyte injury, and interstitial inflammation.
Machado
Flavia Gomes
FG
Laboratory of Renal Pathophysiology, Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of Sao Paulo, São Paulo, Brazil.
Poppi
Elizabete Pereira Barros
EP
Fanelli
Camilla
C
Malheiros
Denise Maria Avancini Costa
DM
Zatz
Roberto
R
Fujihara
Clarice Kazue
CK
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006977:Hypertension, Renal / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D007774:Lactation; D019808:Losartan / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology
D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D019808:Losartan