Aims: 

NO-deficiency and the pro-fibrotic cytokine TGF-ß play an important role in the progression of renal disease in diabetes. In the initial phase this is characterized by renal hyperfiltration. In the current study we tested the hypothesis that limitation of NO bioviability and induction of TGF-ß1 are sufficient to induce hyperfiltration in vivo in the absence of diabetes.

Methods: 

Mice with a constitutive hepatic release of active TGF-ß1 were crossed with eNOS knock out mice resulting in eNOS heterozygous mice either not overexpressing TGF-ß1 (eNOS+/­) or overexpressing TGF-ß1 (eNOS+/­XTGF-ß1-TG). Creatinin serum level, kidney weight to body weight ratio (KW/BW), and renal expression of fibrotic markers (quantitative real-time RT-PCR) were determined at the age of 6 months.

Results: 

29 eNOS+/­ mice were analyzed. 7 of them (24%) developed a mild disease (mean distress score: 3.7), mild reduction of serum creatinine levels (n.s.) which did not correlate with the level of illness, but remained normal KW/BW. Although renal disease is not obvious in these mice, TGF-ß1, decorin, and ornithine decarboxylase (ODC) were induced in all healthy mice compared to non-transgenic controls but not in the 7 mice with mild disease. In contrast, renal laminin expression was significantly reduced in eNOS+/­ with mild disease compared to healthy mice. Next, 21 eNOS+/­XTGF-ß1-TG mice were analyzed. 4 of them (19%) developed severe illness (mean distress score: 7.0). These had significantly reduced serum creatinine levels as an indicator of hyperfiltration and elevated KW/BW. A hyperinduction of ODC and a signifiant induction of TGF-ß1 was measured in all TGF-ß1 transgenic mice (including mice with normal eNOS expression) but no differences in any of the pro-fibrotic markers and no correlation between hyperfiltration and normal kidney function.

Conclusion: 

TGF-ß1 overexpression is indeed associated with a higher risk for renal dysregulation as indicated by hyperfiltration in mice that have only one eNOS allele. However, a constitutively elevated expression of pro-fibrotic markers is not associated with these findings.