Renal expression of mRNAs for endothelin-1, endothelin-3 and endothelin receptors in NZB/W F1 mice.

Endothelin (ET)-1, ET-3, and ET receptors are widely distributed in the vascular system and the kidney. The present study was designed to measure the renal concentrations of ET-1, ET-3, and ET receptor mRNAs in NZB/W F1 mice at 8, 24, and 48 weeks of age. The renal concentration of ET-1 mRNA increased significantly in NZB/W F1 mice as their nephritis progressed, reaching, by 48 weeks, a 10-fold higher concentration than in control NZW mice. Renal ET-3 mRNA concentrations, however, remained unchanged. The renal concentrations of ET receptor A and B mRNAs in NZB/W F1 mice increased gradually with the progression of nephritis, reaching 5- and 3-fold higher concentrations, respectively, at 48 weeks of age than found in control mice. Transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha) have been shown to stimulate ET-1 mRNA expression in cultured mesangial cells. We therefore also examined the concentrations of TGF-beta and TNF-alpha mRNAs in the renal tissues of NZB/W F1 mice, and found that, at 48 weeks of age, they were 10- and 8-fold higher, respectively, than in control NZW mice. At 24 weeks, NZB/W F1 mice were divided into two groups receiving either methylprednisolone (MPSL) or saline injections for the following 24 weeks. The development of the histologic lesions characteristic of lupus nephritis and the increased renal concentrations of ET-1, ET receptors, TGF-beta and TNF-alpha mRNAs were suppressed by MPSL treatment. These data suggest that ET and ET receptor gene transcription is upregulated in the renal tissues of NZB/W F1 mice and that the beneficial treatment of lupus nephritis with MPSL is accompanied by a reduction in the elevated concentrations of ET-1, ET receptors, TGF-beta and TNF-alpha mRNAs.