Endothelin A Receptor Blockade Influences Apoptosis and Cellular Proliferation in the Developing Rat Kidney

Abstract

Endothelin systems are believed to play important roles in the emergence and maintenance of functions of various organs during perinatal development, including the kidney. The present study was designed to investigate the roles of endothelin systems on physiologic renal growth and development. Newborn rat pups were treated with either Bristol-Myers Squibb-182874 (30 mg/kg/day), a selective endothelin A receptor (ETAR) antagonist, or vehicle for 7 days. To identify cellular changes, kidneys were examined for apoptotic cells by terminal deoxynucleotide transferase-mediated nick-end labeling stain and proliferating cell nuclear antigen (PCNA) by immunohistochemical (IHC) stain. To clarify the molecular control of these processes, immunoblots and reverse transcriptase-polymerase chain reaction for Clusterin, Bcl-2, Bcl-XL, Bax, and p53 were performed. ETAR antagonist treatment resulted in reduced kidney weights, decreased PCNA-positive proliferating cells, and increased apoptotic cells. The protein expressions of renal Bcl-XL and Bax in the ETAR antagonist-treated group were significantly decreased, whereas the mRNA expressions of these genes were not changed. There were no significant differences in the expressions of Clusterin, Bcl-2, and p53. In conclusion, inhibition of endogenous endothelins impairs renal growth, in which decreased cellular proliferation, increased apoptosis and decreased expressions of renal Bcl-XL and Bax are possibly implicated.

Repeated Administration of Centhaquin to Pregnant Rats did not Affect Postnatal Development and Expression of Endothelin Receptors in the Brain, Heart or Kidney of Pups

“…The eff ect of centhaquin on prenatal and postnatal development has not been studied. It has been advocated that the endothelin (ET) system plays an important role in the emergence and maintenance of various organs and their functions during prenatal development [ 8 ] . Targeted disruption of ET-1 gene in mouse embryonic stem cells led to death of these mice at birth due to respiratory failure and produced malformation of craniofacial tissues, indicating the involvement of ET-1 in normal ontogeny [ 9 ] .…”

Endothelium-derived ET-1 and the development of renal injury

“…Several publications report that ET A receptor activation promotes cell proliferation and cell survival in a rat model of polycystic kidney disease (PKD) (16) during kidney development (41), in vascular smooth muscle cells (34), or in cardiomyocytes (27), whereas others describe pro-apoptotic effects of the ET A receptor in a model of chronic renovascular disease (19). Furthermore, ET Bselective agonists decreased apoptosis in rat endothelial cells (33) and ET B antagonists lead to increased apoptosis in rat and human endothelial cells (11,32).…”

Apoptosis in the kidneys of rats that experienced intrauterine growth restriction

“…Apoptosis has been associated with the reduction in renal glomerular number in a rat IUGR model induced by bilateral uterine artery ligation . Imbalance between proliferation and apoptosis has been widely known to play an important role in a variety of physiological processes, such as embryonic growth, development, proliferation of cells, or in a variety of pathological processes such as autoimmune diseases, tumours, and organ damage . A variety of adverse factors, such as hypoxia and malnutrition, can break the balance between apoptosis and proliferation and cause pathological changes in the kidneys, such as reducing the number of glomeruli .…”

“…13,14 Imbalance between proliferation and apoptosis has been widely known to play an important role in a variety of physiological processes, such as embryonic growth, development, proliferation of cells, or in a variety of pathological processes such as autoimmune diseases, tumours, and organ damage. 24 A variety of adverse factors, such as hypoxia and malnutrition, can break the balance between apoptosis and proliferation and cause pathological changes in the kidneys, such as reducing the number of glomeruli. 9,25 In this study, no significant difference in the proliferation index was observed between IUGR pups and control pups whose mothers were fed a normal diet.…”