The molecular mechanisms of collagen VIII-dependent gender differences in the development of diabetic nephropathy

• Applicant: Privatdozentin Dr. Ivonne Loeffler
• Subject Area: Nephrology ; Endocrinology, Diabetology, Metabolism
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 405579639

The Nature edition no. 465 in the year 2010 published a series of commentaries and articles urging to include the gender in the agenda. Until now the biomedical research has focused mainly on male test subjects in detriment of females and the straightforward extrapolation of transfer of the male data to the female organism is, in many cases, probably simply wrong. The differences between both genders together with their distinct susceptibility for diseases are known for decades. These sex differences are also described for diabetic nephropathy (DN), the prime late sequel of diabetes mellitus. Heretofore there are only a few studies investigating the molecular causes of the gender effects, in other words, assessing the influence of sexual hormones on DN. The pathophysiology of DN is very complex, but many mechanism of the development and progression of DN have been identified. Within the scope of our studies of DN we focused on the matrix protein collagen VIII (Col8). Col8 is very markedly increased in the kidney of patients with DN pointing to a possible pathophysiological function of Col8 in DN. Follow-up animal studies with Col8 knockout mice confirmed these data: type 1 diabetic mice without col8 expression (knockout) showed a significantly reduced manifestation of DN compared with the diabetic mice carrying the Col8 wildtype allele. In these analyses we used exclusively male animals animals in order to avoid interference by the menstrual cycle. The next step was to study whether the Col8 knockout is also renoprotective in the case of type 2 diabetes mellitus induced DN. In these experiments we compared male and female animals. Interestingly, female Col8 knockout mice were not protected from progression of DN. Quite the contrary, diabetic female mice without Col8 showed exacerbated features of DN compared to the diabetic wildtype female and male mice. These findings were confirmed by the reevaluation of already published data from a small patient cohort with DN.The aim of the current project will be to investigate the mechanisms that are responsible for the Col8-dependent gender effects on DN. For this purpose we will carry out animal experiments and analyse patient biomaterial. To identify the molecular mechanisms at play we will run phosphoproteomic and signal transduction analysis in the context of two cooperations. Of note, many of the experimental readouts will be assessed in an ex-vivo kidney model developed in our laboratory. In summary, our preliminary data reveal a possible, molecular principle of the gender differences in development and progression of DN dependent on Col8. Beyond the mere conceptual advances, gaining insight into the mechanisms of Col8-dependent processes during DN will shed light on the often fatally neglected aspect of gender differences in human pathologies.

• DFG Programme: Research Grants
• Co-Investigators: Privatdozent Dr. Martin Andreas Busch; Professor Dr. Ralf Mrowka