Role of TRPV1 renal sensory nerves in chronic kidney disease

摘要

ABSTRACT CKD is characterized by irreversible kidney damage, worsening renal function, and sympathetic activation. Renal nerve denervation improves kidney function in CKD patients. These effects are partly attributed to altered renal afferent (sensory) nerve activity (ARNA). Renal sensory nerves sense changes in the chemical milieu of the kidney and reflexively modulate sympathetic outflow to maintain kidney homeostasis. The pathogenic contribution of renal sensory nerves in the development of CKD is poorly defined. TRPV1 channels are expressed in renal sensory nerves and the TRPV1 agonist capsaicin increases ARNA and renal sympathetic nerve activity. TRPV1 is a nonselective cation channel that responds to noxious stimuli, pH, and chemokines. Moreover, persistent inflammation is a pathologic hallmark of CKD and TRPV1 channels promote inflammation in experimental models of pain and nephropathy. Therefore, my core hypothesis is that TRPV1-expressing renal afferent nerves are overactive and sensitized in CKD to subsequently elevate renal SNA and reduce GFR. Chronically, TRPV1-expressing renal afferent fibers sense renal cytokines and contribute to renal inflammation that further elevate renal SNA and reduces GFR–worsening CKD progression. This hypothesis will be tested using “state-of-the-art” neurophysiological approaches and novel TRPV1-flox and TRPV1- Cre transgenic rat lines. Single unit recordings and single-cell transcriptomics will be employed in parallel to examine the identity of TRPV1 and non-TRPV1 expressing neurons and link them with their activity in CKD. Optogenetics and transgenic rats will be used to test the extent by which TRPV1-expressing renal sensory fibers or TRPV1 channels influence renal efferent SNA and renal function in CKD. Lastly, renal cytokine-evoked ARNA responses will be evaluated and their impact on renal SNA and renal hemodynamics will be tested. Completion of these aims will 1) identify novel renal sensory nerve populations that directly contribute to renal dysfunction and inflammation in CKD and 2) provide support for establishing an independent research program focused on the neural control of kidney function in renal disease such as CKD.