Thyroglobulin (Tg), has recently been identified as a transcriptional regulator of thyroid-restricted genes. The extrathyroidal expression of several of these genes (including the transcription factor Pax-8) together with the occurrence of specific Tg binding sites suggests a secondary role for Tg as a circulating hormone. In this study, we demonstrate using Northern analysis that Pax-8 is expressed in the mouse mesangial cell, and that its transcript levels are suppressed by Tg. These cells also express an asialoglycoprotein receptor, a receptor involved in Tg endocytosis in the thyroid, and a Tg transcript smaller than the 8.3-kb thyroidal form. Reverse transcriptase PCR showed that suppression of Pax-8 by Tg is correlated with reduced expression of bcl-2 apoptosis suppressor. Tg, but not triiodothyronine (T-3) significantly increased MC proliferation above control as determined by DNA content of MC cultures. The effect of Tg on proliferation was not duplicated by either bovine serum albumin, gamma -globulins, lactoferrin, or the ASGPR-specific ligand, orosomucoid. These results suggest a possible endocrine role for Tg in regulating both Pax-8 related gene transcription and cell division in the mesangial cell.