Effects of diabetes and hypertension on glomerular transforming growth factor-beta receptor expression

Background. Several studies have suggested that transforming growth factor- beta 1 (TGF-beta 1) is an important determinant of diabetic glomerular inju ry. TGF-beta 1 forms a heteromeric complex with two cellular receptor subty pes, designated TGF-beta RII and TGF-beta RI, but the effects of diabetes m ellitus on glomerular TGF-beta receptor expression have not been completely elucidated. We first compared the effect of experimental type I diabetes m ellitus and uninephrectomy on glomerular TGF-beta receptor expression in sp ontaneously hypertensive rats (SHRs), and then sought to determine whether changes in TGF-beta receptor expression were strain specific by studying no rmotensive Wistar-Kyoto (WKY) rats. Methods. Five groups of male SHRs were studied. The first group received st reptozotocin (60 mg/kg IV) and was studied after one week. The second group received streptozotocin and was studied after two weeks. The third group r eceived streptozotocin (60 mg/kg IV) but received insulin to maintain eugly cemia. The fourth group of age-matched SHRs served as the control group, wh ile a fifth group of SHRs underwent uninephrectomy. Four groups of male WKY rats were also studied. The first group of WKY rats served as the age-matc hed control group. The second group of WKY rats received streptozotocin, wh ile a third group of WKY rats underwent uninephrectomy. The fourth group un derwent uninephrectomy and received streptozotocin. At each time point, glo meruli were isolated for protein extraction, and the protein was subjected to Western blot analysis of TGF-beta RII and TGF-beta RI expression. Results. Basal expression of both TGF-beta receptors per microgram of glome rular protein was similar in normotensive WKY rats and hypertensive SHRs. H yperglycemia (blood glucose level, 17.5 +/- 29 mmol/L) led to an early twof old increase in TGF-beta RII protein expression and a fourfold increase in TGF-beta RI protein expression in the glomeruli of hypertensive diabetic SH Rs compared with euglycemic SHRs (blood glucose level, 5.8 +/- 0.8 mmol/L), which was sustained after two weeks. Insulin treatment (blood glucose leve l, 5.2 +/- 0.9 mmol/L) normalized both TGF-beta RII and TGF-beta RI express ion in the glomeruli of SHRs that received streptozotocin. Glomerular capil lary hypertension in the uninephrectomized SHRs led a twofold increase in g lomerular TGF-beta RII protein expression, but did not reproduce the effect of diabetes mellitus on TGF-beta RI expression. In contrast to the finding s in SHRs, neither hyperglycemia (blood glucose level; 15.5 +/- 2.1 mmol/L) , uninephrectomy, nor hyperglycemia (blood glucose level, 16.8 +/- 3.0 mmol /L) and uninephrectomy altered TGF-beta receptor expression in the glomerul i of normotensive WKY rats. Conclusion. These studies support the hypothesis that hemodynamic factors a nd metabolic factors influence glomerular TGF-beta receptor in vivo in the SHRs.