Rapamycin Slows IgA Nephropathy Progression in the Rat

Abstract

Background: IgA nephropathy (IgAN) is the most frequent glomerulonephritis worldwide. Different therapeutic approaches have been tested against IgAN. The present study was designed to explore the renoprotective potential of low-dose mammalian target of rapamycin (mTOR) inhibitor rapamycin in an IgAN rat model and the possible mechanism of action. Methods: After establishing an IgAN model, the rats were randomly divided into four groups: control, control with rapamycin treatment, IgAN model, and IgAN model with rapamycin treatment. Coomassie Brilliant Blue was utilized to measure 24-hour urinary protein levels. Hepatic and renal function was determined with an autoanalyzer. Proliferation was assayed via 5-bromo-2′-deoxyuridine incorporation. Real-time PCR and immunohistochemistry were utilized to detect the expression of α-SMA, collagen I, collagen III, TGF-β₁ and platelet-derived growth factor. Western blotting and immunohistochemistry were performed to determine p-S6 protein levels. Results: Low-dose mTOR inhibitor rapamycin prevented an additional increase in proteinuria and protected kidney function in a model of IgAN. Rapamycin directly or indirectly interfered with multiple key pathways in the progression of IgAN to end-stage renal disease: (1) reduced the deposition of IgA and inhibited cell proliferation; (2) decreased the expression of fibrosis markers α-SMA and type III collagen, and (3) downregulated the expression of the profibrotic growth factors platelet-derived growth factor and TGF-β₁. The expression of p-S6 was significantly elevated in IgAN rats. Conclusions: The mTOR pathway was activated in IgAN rats and the early application of low-dose mTOR inhibitor rapamycin may slow the renal injury of IgAN in rats.