AT₁ blockade during lactation as a model of chronic nephropathy: mechanisms of renal injury

Abstract

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.

Programmed hypertension in rats treated with a NF-κB inhibitor during nephrogenesis: renal mechanisms

“…Unlike previous observations with neonatal losartan, 6 rats treated with PDTC during lactation showed no gross renal structural abnormalities. However, other findings clearly indicate that PDTC did reach the pups through maternal milk.…”

“…Further details of these procedures are given elsewhere. 6 Histomorphometric measurements for assessment of glomerular injury and interstitial expansion were performed by a single observer (DMACM) who was blinded to the groups. For each rat, the percentage of glomeruli exhibiting sclerotic lesions was estimated in sections stained by the periodic acid-Schiff reaction.…”

“…17 The total diameter and wall thickness of periglomerular arterioles was measured by a single observer blinded to the groups under Â200 magnification, with the aid of a micrometric scale (2.5 mm smallest division). Immunohistochemical analysis was performed utilizing conventional methods, 6 employing a polyclonal goat anti-angiotensinogen antibody (Santa Cruz Biotechnology, Santa Cruz, CA, USA) to detect the presence of cortical angiotensinogen (AGT) in renal tissue. The percentage of cortical area staining positive for AGT was quantified blindly with the aid of an image processing software (Image Pro Plus, Media Cybernetics, Bethesda, MD, USA).…”

“…However, the study of the pathogenesis of blood pressure elevation in these rats is complicated by the concomitant development of severe and progressive glomerular and renal interstitial injury. [4][5][6][7] Several of the inflammatory effects of angiotensin II in adult life are mediated, at the intracellular level, by the nuclear factor NF-kB system. [8][9][10][11] Accordingly, continuous inhibition of this system exerts a protective effect in an experimental model of chronic kidney disease.…”

Roles of mitogen-activated protein kinases and angiotensin II in renal development

“…Machado et al (39) observed that rats that received losartan during lactation presented albuminuria and alterations in renal structure in adult life that were related to the presence of an inflammatory infiltrate in the renal cortex. We observed that the 30-day-old pups from dams treated with losartan during lactation presented increased AT 2 , p-JNK and p-p38 expression in the kidneys and higher numbers of TUNEL (apoptosis) and PCNA-positive cells in the renal cortex (40).…”