The Role of MCP-1 in Tubular-to-Glomerular Crosstalk in Proteinuric Kidney Disease

ABSTRACT
Chronic kidney disease (CKD) is defined as kidney damage or reduction in glomerular filtration rate for three
months or more, irrespective of cause. CKD affects an estimated 276 million people worldwide, leads to reduced
quality of life and increased morbidity, mortality, and healthcare costs. For many, CKD progresses to end-stage
renal disease (ESRD) and the need for dialysis and transplantation. Abnormal leak of protein into the urine (i.e.,
proteinuria) is associated with a worse prognosis and greater likelihood of progression to ESRD. While
proteinuric diseases are generally studied as a disease of the glomeruli and resident podocytes, we propose that
the renal tubules may also play a key role in promoting glomerular proteinuria. β-catenin is a transcription factor
active in tubular epithelia during kidney injury. Preliminary data show that tubule-specific β-catenin knockout
mice are protected from glomerular injury and proteinuria, suggesting that tubules can play a role in glomerular
disease. This protection was associated with reduced expression of monocyte chemoattractant protein-1 (MCP-
1), and MCP-1 is known to adversely affect the resident podocytes of the glomerulus. Therefore, we hypothesize
that tubular-to-glomerular crosstalk in response to injury involves the β-catenin-mediated release of MCP-1 from
kidney tubules. This hypothesis will be tested through three aims. First, we will investigate the effect of β-catenin
on inducing MCP-1 expression in renal tubules. Second, we will assess the effect of MCP-1 on slit diaphragm
integrity. Third, we will investigate the contribution of tubule-specific MCP-1 in the development of glomerular
injury and podocyte dysfunction. This proposal will provide Dr. Bondi with the opportunity to acquire additional
experience with rodent models of kidney injury, establishing conditional genetic knockout mouse models, kidney
imaging, performing and analyzing data from both ChIP and ChIP-seq experiments as well as staying abreast of
the rapid, technological advances in molecular technologies. Dr. Bondi will personally interact with and be
mentored by a team of accomplished and experienced mentors, advisors, and collaborators to ensure successful
completion of the proposal. By having the K01 support, Dr. Bondi will be able to take advantage of core
resources, workshops, and courses offered within and outside of the University of Pittsburgh. Dr. Bondi will
use this proposal to accomplish the short-term goal of acquiring additional technical and professional training,
and the long-term goal of becoming a leading primary investigator-educator in kidney disease with a fully-funded
laboratory, which maintains productivity, fosters collaborations, and provides mentorship. Overall, the results
from this proposal will not only form the basis for a R01 study but will lead to a new understanding of CKD and
provide important mechanistic data that is critical for the development of future therapeutic interventions for
proteinuric CKD.

Grant Number: 5K01DK124357-05
NIH Institute/Center: NIH
Principal Investigator: Corry Bondi