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Renal nerves drive interstitial fibrogenesis in obstructive nephropathy.

Kim J, Padanilam BJ.

J Am Soc Nephrol. 2013 Feb;24(2):229-42.

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5850, USA.

 

Abstract

The signals that drive fibrogenesis after an initiating insult to the kidney are incompletely understood. Here, we report that renal nerve stimulation after ureteral obstruction is the primary profibrotic signal and that renal denervation prevents both fibrogenesis and the inflammatory cascade. Local infusion of neural factors, norepinephrine, and calcitonin gene-related peptide (CGRP) in denervated kidneys mimicked the fibrotic response observed in innervated obstructed kidneys. Norepinephrine and CGRP act through the {Alpha}(2)-adrenergic receptor and CGRP receptor, respectively, because blocking these receptors prevented fibrosis, the inflammatory response, and tubular cell death. In tubular epithelial cells, both norepinephrine and CGRP induced apoptosis and the release of profibrotic factors capable of stimulating the differentiation of fibroblasts to myofibroblasts. In conclusion, these data suggest that nerve-derived signaling molecules may drive renal fibrosis and that their suppression may be a therapeutic approach to fibrosis prevention.

 

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Additional Information

Although fibrogenesis is the final common pathway that leads to end-stage renal disease, there is little information available regarding the primary signals that drive fibrogenesis. Our studies indicate the novel paradigm that renal denervation can prevent renal fibrosis and inflammation in obstructive nephropathy. This result suggests that renal nerve stimulation may be the primary mechanism and nerve-derived factors may play key role in instigating fibrogenesis and inflammation in the kidney.

Based on our data, the release of two neuropeptides, calcitonin gene-related peptide (CGRP) and norepinephrine (NE), are required to instigate fibrogenesis. The NE and CGRP released by the renal nerves may activate apoptotic/necrotic, fibrogenic and inflammatory signaling pathways in various renal cells with the ensuing tubular atrophy, inflammation and myofibroblast differentiation resulting in progression of fibrosis and chronic kidney disease.  Inhibition of CGRP and/or NE or intervening in their signaling pathways may offer opportunities to design novel therapeutic approaches to treat chronic kidney disease.

Figure legend

A schema of the proposed Nerve-induced signaling pathway leading to interstitial fibrogenesis.

Renal Nerves Drive Interstitial Fibrogenesis in Obstructive Nephropathy