Postnatal renal abnormalities in rats exposed to losartan during lactation.

BACKGROUND/AIMS: Rats exposed to losartan during lactation exhibit progressive changes in renal function and structure. This study analyzed the early events in pups from dams that received losartan during lactation. METHODS: Male Wistar rats from dams that received 2% sucrose (control, n = 25) or losartan (100 mg/kg/day) diluted in 2% sucrose (n = 33) during lactation were anesthetized 21 days after birth. Blood and urine samples were collected to assess renal function, and kidneys were removed for histological, immunohistochemical, Western blot, lipid peroxidation and glutathione analyses. RESULTS: The group exposed to losartan exhibited increased albuminuria and fractional sodium and potassium excretion, decreased glomerular area and interstitial expansion. Immunohistochemical analyses demonstrated increased tubulointerstitial macrophage infiltration, apoptosis and increased vimentin and α-smooth-muscle-actin expression in animals exposed to losartan. In addition, the glomeruli of animals exposed to losartan exhibited increased peripheral desmin expression and reduced glomerular epithelial protein 1 and podocin expression compared to controls. Lastly, renal lipid peroxidation and glutathione levels were higher in the losartan-treated pups. CONCLUSION: Pups exposed to losartan during lactation exhibited adverse changes in renal function and structure, and tubulointerstitial inflammation at 21 days of age that were associated with apoptosis and oxidative stress.

Prenatal blockade of Ang II receptors affects neonatal rat hindbrain structure and receptor localization.

The development of knock-out mice for Angiotensin II (Ang II) AT(2) receptors, which exhibited altered exploratory behavior, prompted us to investigate the cerebellum and brainstem. We evaluated the effect of stimulation/inhibition of Ang II receptors on hindbrain development, in offspring (postnatal days P0, P8) of pregnant rats treated during late pregnancy (Ang II, Losartan or PD123319, 1 mg/kg/day). Receptor localization by autoradiography showed in P0 and P8 hindbrains, that most structures expressed AT(2) subtype: cerebellar cortex, cerebellar nuclei, genu facial nucleus, inferior colicullus, inferior olive. In the cerebellar cortex, [(125)I]Ang II AT(2) binding was predominant, while low AT(1) binding was observed in adjacent layers of the cerebellar cortex. Blockade of AT(2) receptors with PD123319 increased binding in cerebellar nuclei (p<0.05) and brainstem nuclei at P0, P8, in correlation with increased AT(2) receptor expression by RT-PCR. The enlarged external granular layer (EGL) in PD123319-treated P0 pups contrast with the significant decrease in Ang II binding (p<0.001) in the cerebellar cortex. Blockade of AT(2) receptors during late pregnancy seems to arrest cerebellar cortex development in P0 animals. On the contrary, increased AT(2) binding was observed in cerebellar cortex and DTg nucleus in PD123319-treated P8 animals (p<0.001). Ang II treatment leads to increased binding in the brainstem. In spite of the low doses of Ang II antagonists used, treatments were performed during a time-frame critical for hindbrain development, leading to remarkable effects. The present study makes a contribution to understand the role of Ang II receptors during hindbrain development.

Inhibition of Angiotensin II receptors during pregnancy induces malformations in developing rat kidney.

Evidence suggests that Angiotensin II plays an important role in the complex process of renal organogenesis. Rat kidney organogenesis starts between E13-14 and lasts up to 2 weeks after birth. The present study demonstrates histologic modifications and changes in receptor localisation in animals born from mothers treated with Angiotensin II, Losartan or PD123319 (1.0 mg/kg/day) during late pregnancy. Angiotensin II-treated animals exhibited very well developed tubules in the renal medulla in coincidence with higher AT(1) binding. Control animals exhibited angiotensin AT(2) binding in the outer stripe of the outer medulla, while in the Angiotensin II-treated animals binding was observed to the inner stripe. In Angiotensin II-treated 1-week-old animals, the nephrogenic zone contained fewer immature structures, and more developed collecting tubules than control animals. Treatment with Losartan resulted in severe renal abnormalities. For newborn and 1-week-old animals, glomeruli exhibited altered shape and enlarged Bowman spaces, in concordance with a loss of [(125)I]Angiotensin II binding in the cortex. Blockade with PD123319 led to an enlarged nephrogenic zone with increased number of immature glomeruli, and less glomeruli in the juxtamedullary area. Autoradiography showed a considerable loss of AT(1) binding in the kidney cortex of PD123319-treated animals at both ages. The present results show for the first time histomorphological and receptor localisation alterations following treatment with low doses of Losartan and PD123319 during pregnancy. These observations confirm previous assumptions that in the developing kidney Angiotensin II exerts stimulatory effects through AT(1) receptors that might be counterbalanced by angiotensin AT(2) receptors.