Ion-Channel modulator TH1177 reduces glomerular injury and serum creatinine in chronic mesangial proliferative disease in rats

Abstract

Background: 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. 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. Methods: Chronic 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. Results: Treatment 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. Conclusions: The 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.

Stimulated phosphorylation of ERK in mouse kidney mesangial cells is dependent upon expression of Cav3.1

“…TTCC and their role in MC proliferation have been reported in a few studies. Findings in rat and human MC have shown that only Ca V 3.1 and Ca V 3.2 were detected in rat MC and Ca V 3.2 is expressed in human MC [12][13][14]. However, in our study, we have shown that all three TTCC isoforms (Ca V 3.1, Ca V 3.2 and Ca V 3.3) were The full-length images of Western blot are presented in Supplementary figure S6.…”

“…The specific target of these actions is uncertain, though they are unlikely to be P/Q-type, N-type or R-type calcium channels as there is no evidence of their expression in MC. TTCC on the other hand, are expressed in human and rat MC and are sensitive to inhibition by the TTCC blocker TH1177 in vitro and in vivo in the Thy1 nephritis rat model [12,13]. Also, the knockdown of TTCC in human and rat MC has been shown to inhibit proliferation [12,14].…”