Endothelin A receptor blockade decreases expression of growth factors and collagen and improves matrix metalloproteinase-2 activity in kidneys from stroke-prone spontaneously hypertensive rats.
This study hypothesizes that endothelin-1 induces renal damage by increasing expression of growth/inflammatory factors, important in renal fibrosis. Male stroke-prone spontaneously hypertensive rats (SHRSPs) (8-weeks, n = 24) were randomized into three groups: control group, high-salt group (4% NaCl), and salt plus an endothelin A receptor antagonist, BMS 182874 (40 mg/kg/d). After 20 weeks treatment, rats were killed. Messenger RNA (mRNA) expression of renal preproendothelin-1, endothelin A and B receptors, and procollagen I and III was evaluated by reverse transcription polymerase chain reaction. Expression of transforming growth factor (TGF)-beta1 and basic fibroblast growth factor (bFGF) was determined by immunoblotting. Matrix metalloproteinase-2 (MMP-2) activity was measured by zymography. In salt-loaded SHRSPs, preproendothelin-1 mRNA expression was increased 1.6-fold, and endothelin A receptor mRNA expression was decreased (70% of control). Salt-loaded SHRSPs had increased renal expression of TGF-b1 and procollagens. MMP-2 activity was augmented fivefold. BMS decreased (p < 0.01) expression of TGF-beta1, bFGF, and procollagen I and reduced MMP-2 activity. Thus severe hypertension and renal dysfunction in salt-loaded SHRSPs are associated with increased expression of renal endothelin-1, growth factors, and collagen. BMS treatment alleviated these effects, suggesting that nephroprotection by endothelin A receptor blockade is mediated by normalizing expression of growth factors, reducing extracellular matrix deposition, and decreasing MMP activity.
Tostes
Rita C A
RC
University of Sao Paulo, Institute of Biomedical Science, Department of Pharmacology, SP, Brazil.
Touyz
Rhian M
RM
He
Gang
G
Ammarguellat
Fatima
F
Schiffrin
Ernesto L
EL
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D003094:Collagen / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D065128:Endothelin Receptor Antagonists; D006133:Growth Substances / Q000096:biosynthesis / Q000378:metabolism*; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000096:biosynthesis / Q000502:physiology*; D020521:Stroke / Q000188:drug therapy / Q000201:enzymology*
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D006133:Growth Substances; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D003094:Collagen; D020778:Matrix Metalloproteinase 2