Endothelin A receptor blockade influences apoptosis and cellular proliferation in the developing rat kidney.
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 (ET(A)R) 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-X(L), 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-X(L) 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-X(L) and Bax are possibly implicated.
Yoo
Kee Hwan
KH
Department of Pediatrics, College of Medicine, Korea University, Seoul, Korea.
Yim
Hyung Eun
HE
Jang
Gi Young
GY
Bae
In Sun
IS
Choi
Byung Min
BM
Hong
Young Sook
YS
Lee
Joo Won
JW
D000818:Animals; D000831:Animals, Newborn; D000959:Antihypertensive Agents / Q000494:pharmacology*; D017209:Apoptosis; D049109:Cell Proliferation; D003619:Dansyl Compounds / Q000494:pharmacology*; D065130:Endothelin A Receptor Antagonists; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
D000959:Antihypertensive Agents; D003619:Dansyl Compounds; D065130:Endothelin A Receptor Antagonists; D018809:Proliferating Cell Nuclear Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D044022:Receptor, Endothelin A; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; C085754:5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide