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Neonatal RAS inhibition changes the phenotype of the developing thick ascending limb of Henle

¹Department of Physiology, Institute of Physiology and Pharmacology, and ²Department of Clinical Physiology, University of Gothenburg, 413 90 Gothenburg; and ³Department of Pathology and Cytology, Karolinska Hospital, 171 76 Stockholm, Sweden

Submitted 30 June 2003 ; accepted in final form 4 February 2004

Pharmacological interruption of angiotensin II type 1 (AT₁) receptor signaling during nephrogenesis in rats perturbs renal tubular development. Perturbed tubulogenesis may contribute to long-term impairment of urinary concentrating ability, which is the main functional irreversible defect. The aim of this study was to further characterize tubular developmental deficits in neonatal rats, focusing on the thick ascending limb of Henle (TALH), known to undergo profound developmental changes and to be involved in urine-concentrating mechanisms. We have carried out immunohistochemistry and Western immunoblotting using antibodies directed against the major histocompatibility complex class II (MHC II) molecule and different TALH-specific markers, namely, cyclooxygenase-2 (COX-2), Tamm-Horsfall glycoprotein (THP), and the bumetanide-sensitive Na⁺-K⁺-2Cl^– cotransporter (BSC-1/NKCC2). Immunohistochemistry demonstrated expression of MHC II, COX-2, THP, and BSC-1/NKCC2 proteins in normally developing TALH cells. The AT₁-receptor antagonist losartan abolished MHC II expression exclusively in the developing TALH cells. Increased expression of COX-2 and THP was observed in the TALH cells of losartan-treated rats. Western immunoblotting confirmed increases in cortical and medullary COX-2 and THP abundance and revealed a decrease in cortical BSC-1/NKCC2 abundance in response to losartan treatment. We conclude that neonatal losartan treatment causes significant changes in the phenotype of the developing TALH in the rat.

renal development; AT₁ receptor blockade; major histocompatibility complex class II molecule; cyclooxygenase-2; Tamm-Horsfall glycoprotein; bumetanide-sensitive sodium-potassium-chloride cotransporter

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