Chapter 5 98 Figure 4. Increased dynamin expression precedes proteinuria Flow chart illustrating the proposed compensatory mechanism in response to impaired integrity of the glomerular filtration barrier, in which increased dynamin expression precedes proteinuria. After damage to the glomerular filtration barrier, DNM1 and DNM2 are upregulated, leading to increased levels of DNM1 and DNM2 mRNA. Whether this increase results in increased levels of dynamin protein depends upon the oligomerization status of dynamin and the activity of cathepsin L, which selectively cleaves non-oligomerized dynamin.(13) If the total amount of dynamin is sufficient, the glomerular filtration barrier remains intact, preventing the onset of proteinuria. However, if dynamin levels are insufficient—and/or if this compensatory response is exhausted— proteinuria develops. The suggested mechanisms of cytoskeletal architecture maintenance and nephrin turnover have been reported by others. (11-14, 75, 87-89) Dynamin also directly interacts with the actin cytoskeleton, as shown by others.(1113, 75) Consistent with this structural role, our microarray analysis revealed additional evidence that the cytoskeletal architecture is disrupted in Dahl rats, given the differential regulation of cytoskeleton-related genes. Further studies will likely provide new insight into how the actin cytoskeleton is regulated under proteinuric conditions. In conclusion, our results provide evidence that dynamin expression is increased in human proteinuric disease. Moreover, we propose that a minimum level of dynamin is required for GFB integrity, and increases in Dnm1 and Dnm2 mRNA are part of a compensatory mechanism that support GFB integrity under stressful conditions. Given that this mechanism seems to play a role in patients with proteinuric kidney disease, dynamin may represent a promising target for therapeutic intervention.
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