THE BONE MORPHOGENETIC PROTEINS: AN INVESTIGATION INTO THEIR EXPRESSION, REGULATION AND TRANSCRIPTIONALLY DRIVEN RESPONSES IN THE PROXIMAL TUBULE OF THE KIDNEY

Following injury, the kidney has the potential to regenerate damaged tissue. Certain proteins that are members of the Bone Morphogenetic Protein (“BMP”) family have been shown play a significant role in this regeneration as well as in the protection of the kidney from injury. Humans produce approximately one dozen different, but related BMP proteins. These proteins were originally identified as factors that induced the formation of bone, but have subsequently been shown to play a role in numerous developmental and physiological processes. The activities of BMP proteins in the kidney are controlled by numerous regulators. Here we identify the expression of the BMP regulator Chordin-like 1 (“CHRDL1”) in the portion of the kidney most commonly damaged in acute injury – the proximal tubule. Interestingly, the data show that CHRDL1 uniquely antagonizes BMP7, a BMP expressed in a different portion of the kidney – the distal tubule. CHRDL1 expression is temporarily lost following acute injury and this coincides with intense BMP activity in tubules of the recovering kidney. I propose that CHRDL1 reduces BMP7 activity in healthy proximal tubules of the nephron, and that its loss upon injury promotes BMP activity in recovering renal tubules. Following tissue regeneration, CHRDL1 expression returns, re-exerting its antagonistic effect upon BMP7. CHRDL1’s specificity for BMP7, a BMP not produced in the proximal tubule, raises the questions of whether the proximal tubule is producing other BMPs, and if so, why they are not antagonized by CHRDL1. The data show that the proximal tubule expresses two other BMP proteins: BMP2 and BMP4. Our research shows that the response of proximal tubule cells to BMP2 and BMP7 is virtually identical. Our research further shows that certain proteins typically associated with the Notch signaling pathway are induced by exposure to diverse BMP proteins. The data suggest that one of these proteins, HEY1, may function as a negative feedback regulator of BMP2 expression. Finally, a number of novel genes regulated by proximal tubule cells in response to BMP are identified. Investigating these candidates may supplement existing knowledge regarding the mechanisms through which BMPs achieve their renoprotective and therapeutic effect.