Pathogenesis of the concentric hypertrophy of the kidney arterioles

About This Grant

PROJECT SUMMARY/ABSTRACT More than 30% of the US population suffers from hypertension, a leading cause of morbidity and mortality due to cardiovascular and kidney disease. Inhibitors of the renin-angiotensin system (iRAS) are used widely and effectively to treat hypertension. However, chronic stimulation of the renin cells, with iRAS or mutations of any of the renin angiotensin genes leads to concentric arterial and arteriolar hypertrophy (CAAH) a silent, progressive, generalized, and severe thickening of the intrarenal arterial tree. Numerous hypertrophic renin cells surround the arteriolar walls, smooth muscle cells (SMCs) accumulate inwardly, narrowing the vessel lumens and restricting blood flow, resulting in ischemia, fibrosis, and renal failure. Despite its medical importance and the prevalent use of iRAS to treat hypertension, our knowledge of this disease is limited. The condition is intimately linked to the development of renin cells: they are progenitors of SMCs, mesangial cells and pericytes which retain the memory of -and transform to- the renin phenotype in response to homeostatic challenges. Genetic ablation of renin cells prevents the arterial disease indicating that renin cells are responsible by the production of factors that induce the vascular hypertrophy. We found that renin cells produce nerve growth factor (NGF), a powerful guiding molecule that attracts axons to target cells, including renin cells which are exquisitely innervated by thin axons that follow closely the developing arterioles and emit varicosities at the point of contact with the cells. It is likely that innervation regulates the differentiation and fate of renin cells both during arteriolar development and disease. In fact, the diseased vessels are hyper-innervated: numerous and thickened axons wrap around the entire kidney vasculature. As the disease progresses, the arteriolar cells change fate, filtration declines, and new axons arise, transforming the kidney into a pathological neuro-endocrine organ. Our overall hypothesis is that morphogenesis and fate of the renal arterial tree during development and disease are intimately linked and dependent on the co-inductive interactions between nerve fibers and renin cells and their descendants. Using proven tools already developed in our laboratories (novel cell-specific fluorescent reporter mice, 3D imaging, 2-photon microscopy, immuno-EM, innovative surgical techniques, spatial transcriptomics, and time- and cell specific gene deletion studies) we propose to test the following hypotheses: 1. development of the renal arterial tree is coupled with the timely establishment of unique nerve fibers and cell type-specific synapses, 2. innervation and blood flow are necessary for the development of the kidney vasculature and 3. hyperinnervation of the kidney vasculature and NGF are responsible for the CAAH and the transformation of the kidney into a pathological neuro-endocrine organ. This dual PI application composed of a team of experts, based on compelling preliminary data and novel conceptual and technical approaches, will uncover fundamental mechanisms, and solve major gaps in our knowledge that will open new avenues for the development of novel compounds and strategies to protect the kidney while preventing cardiovascular disease.