Abstract
BackgroundT-type calcium channels (TTCC) are involved in mesangial cell proliferation. In acute thy-1 nephritis in the rat TTCC inhibition reduces glomerular damage and cell proliferation. This work is extended here by a study of the non-selective TTCC inhibitor TH1177 in a chronic model of proliferative glomerulonephritis (GN) including late treatment starting after the initial inflammation has resolved. The objective was to determine the effects of TH1177 in a model of chronic mesangioproliferative renal disease.MethodsChronic GN was induced in WKY rats by unilateral nephrectomy (day − 7) followed by day 0 injection of Ox7 thy-1 mAb. Treatment with TH1177 (10–20 mg/Kg daily IP) was started on day 2 (early treatment) or on day 14 (late treatment) and compared to vehicle-treated controls until sacrifice at day 42. Glomerular disease was assessed with a damage score, fibrosis assay, cellular counts and renal function measured by serum creatinine.ResultsTreatment with TH11777 was associated with reduced serum creatinine, less glomerular damage, reduced fibrosis and reduced glomerular cellularity. The results for early and late TH1177 treatments were essentially the same and differed significantly from vehicle.ConclusionsThe ion-channel modulator TH1177 is capable of improving glomerular outcome in chronic rat GN even when treatment starts 14 days after initiation of the disease. These data are discussed in the context of the possible targets of TH1177 including TTCC, TRP family, Stim/Orai group and other cation channels. The work supports the use of genetic models to examine the roles of individual cation channels in progressive glomerulonephritis to further define the targets of TH1177.
Highlights
T-type calcium channels (TTCC) are involved in mesangial cell proliferation
T-type calcium channels (TTCC) are low voltageactivated (LVA) channels that have been shown to play a role in regulating the proliferative rate of non-electrically excitable cells including glomerular mesangial cells (MC) [1,2,3]
We have reported that administration of TH1177 to rats with acute Thy1 nephritis reduces glomerular injury and glomerular cell proliferation in this short-term disease model [5]
Summary
T-type calcium channels (TTCC) are involved in mesangial cell proliferation. In acute thy-1 nephritis in the rat TTCC inhibition reduces glomerular damage and cell proliferation. T-type calcium channels (TTCC) are low voltageactivated (LVA) channels that have been shown to play a role in regulating the proliferative rate of non-electrically excitable cells including glomerular mesangial cells (MC) [1,2,3]. Selective knockdown of these channels in pulmonary artery myocytes [2] and in human MC [3] using siRNA inhibits proliferation. We have reported that administration of TH1177 to rats with acute Thy nephritis reduces glomerular injury and glomerular cell proliferation in this short-term disease model [5] This finding supports the hypothesis that TH1177 may be of benefit in renal diseases that involve excess mesangial cell proliferation
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