This study aims to explore a new mechanism of kidney regeneration which is based on newly identified angiogenic and glomerulotrophic functions of macula densa (MD) cells, and to test its potential therapeutic utility in chronic kidny disease (CKD). Our overall, long-term vision is that a new therapeutic approach, fundamentally different from existing strategies, one that amplifies this novel intrinsic renal repair mechanism, will provide the ultimate cure for this devastating disease. The salt-sensing macula densa (MD) cells of the distal tubule are chief cells within the kidney, strategically positioned at the glomerular entrance, and play key sensory and regulatory functions in body fluid- electrolyte homeostasis. Preliminary work using intravital multiphoton microscopy (MPM) of the same intact kidney region over several days provided visual clues that in response to MD-derived signals, mesenchymal progenitor cells residing in the renal interstitium proliferate and migrate towards the MD, and via the vascular pole into the glomerulus and proximal tubules. Therefore we hypothesize that MD cells are master regulators of renal tissue remodeling, and perform this new, non-traditional function via the generation of novel secreted angiogenic and glomerulotrophic factors, and their paracrine actions on the reactivation and recruitment of mesenchymal progenitor cells. Further, we hypothesize that augmenting these MD mechanisms in CKD may result in rapid tissue remodeling and improved kidney structure and function (regression). This project will use comprehensive experimental approaches including new transgenic mouse models, cell fate tracking, MD transcriptome analysis, bioinformatics, MPM imaging, and a model of focal segmental glomerulosclerosis (FSGS).
The specific aims are to (1) functionally characterize the novel renal tissue remodeling function of MD cells, and to (2) examine the effects of MD activation on kidney structure and function in CKD. These novel MD cell functions may be targeted in the future development of new therapeutic approaches for the better treatment of CKD.
Kidney disease and hypertension are associated with significant comorbidities and mortalities and affect close to a third of the US population, yet ther pathophysiology remains incompletely understood. The juxtaglomerular apparatus (JGA) within the kidney is a key control site of renal and cardiovascular functions and is critically important n the regulation of body fluid and electrolyte homeostasis and blood pressure maintenance. We propose to study novel tissue remodeling and regenerative mechanisms in the JGA using our hallmark imaging approach to better understand the functions of the living kidney in health and disease and to potentially identify new therapeutic targets for kidney disease and hypertension.
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