Diabetologie und Stoffwechsel 2015; 10 - P49
DOI: 10.1055/s-0035-1549555

Podocyte-selective overexpression of the TGF-ß1 receptor type II (TbRII) enhances diabetic nephropathy in STZ induced transgenic rats

T Micakovic 1, R Walz 1, HP Hammes 2, W Kriz 3, SC Hoffmann 1
  • 1Medical Faculty Mannheim, University Heidelberg, Medical Research Center, Mannheim, Germany
  • 2Medical Faculty Mannheim, University Heidelberg, V. Medizinische Klinik., Mannheim, Germany
  • 3Medical Faculty Mannheim, University Heidelberg, CBTM, Mannheim, Germany

Background: Glomerular TGF-ß1 is increased early in the course of diabetic nephropathy. The podocytes are sources and targets of TGF-ß1. This study addresses the hypothesis that increased TGF-ß1 in diabetic rats stimulates the development of diabetic nephropathy via selective signalling in podocytes.

Methods: Transgenic rats carrying the TGRTßRII driven by the podocin promoter were generated. Transgene expression was verified by Northern blotting, in-situ hybridization and Western blotting. Glomerular expression profiling was performed by real time RT-PCR, Western blotting and immunohistochemistry. At 2 months of age rats received STZ (40 mg/kg i.v.) or diluent, respectively. Body weight and kidney function were evaluated by urinary albumin excretion in the 24h urine and by creatinine clearance at monthly intervals.

Results: TGR expressed the transgenic receptor specifically in podocytes. Glomerular TbRII protein levels were almost twice that of WT. At 5 months of age 40% of TGR exhibited moderately increased albumin excretion up to 2.2 mg/24hr vs. 0.11 mg/24hr in WT. 3 months after STZ, albumin excretion was significantly increased in 80% of TGR with an average of 4 mg/24hr (max: 7.3) but only slightly elevated in 40% of WT with in average 0.7 mg/24hr (max: 2.2). Expression profiling in isolated glomeruli revealed significantly down-regulated expression of blc-2, synaptopodin, podocin and nephrin in TGR.

Conclusions: Podocyte-selective TbRII-overexpression contributes to the leakage of the glomerular filter and enhances the development of diabetic nephropathy. Funded by DFG Collaborative Research Center 1118 and by Kidney & Urology Foundation of America KUFA.