Abstract
In the inner ear, cyclic guanosine monophosphate (cGMP) signaling has been described as facilitating otoprotection, which was previously observed through elevated cGMP levels achieved by phosphodiesterase 5 inhibition. However, to date, the upstream guanylyl cyclase (GC) subtype eliciting cGMP production is unknown. Here, we show that mice with a genetic disruption of the gene encoding the cGMP generator GC-A, the receptor for atrial and B-type natriuretic peptides, display a greater vulnerability of hair cells to hidden hearing loss and noise- and age-dependent hearing loss. This vulnerability was associated with GC-A expression in spiral ganglia and outer hair cells (OHCs) but not in inner hair cells (IHCs). GC-A knockout mice exhibited elevated hearing thresholds, most pronounced for the detection of high-frequency tones. Deficits in OHC input–output functions in high-frequency regions were already present in young GC-A-deficient mice, with no signs of an accelerated progression of age-related hearing loss or higher vulnerability to acoustic trauma. OHCs in these frequency regions in young GC-A knockout mice exhibited diminished levels of KCNQ4 expression, which is the dominant K+ channel in OHCs, and decreased activation of poly (ADP-ribose) polymerase-1, an enzyme involved in DNA repair. Further, GC-A knockout mice had IHC synapse impairments and reduced amplitudes of auditory brainstem responses that progressed with age and with acoustic trauma, in contrast to OHCs, when compared to GC-A wild-type littermates. We conclude that GC-A/cGMP-dependent signaling pathways have otoprotective functions and GC-A gene disruption differentially contributes to hair-cell damage in a healthy, aged, or injured system. Thus, augmentation of natriuretic peptide GC-A signaling likely has potential to overcome hidden and noise-induced hearing loss, as well as presbycusis.
Highlights
Hearing loss is considered the fourth leading cause of disability worldwide and is one of the most common conditions affecting older people
Because atrial NP (ANP) and B-type NP (BNP) have emerged as key regulators of energy consumption and metabolism (Ramos et al, 2015), we suggest that guanylyl cyclase (GC)-A signaling in the inner ear is important for metabolic supply as well
We observed strong GC-A staining in outer hair cells (OHCs) (Figure 1A) and no staining in sense controls (Figure 1A)
Summary
Hearing loss is considered the fourth leading cause of disability worldwide and is one of the most common conditions affecting older people. The presbycusis refers to a progressive, age-dependent hearing loss that results from loss of outer hair cell (OHC) function. This decline in OHC function typically begins in regions that respond to high-frequency sounds (Frisina, 2009; Frisina and Frisina, 2013; Lee, 2015). IHC synaptopathy and auditory neuropathy precede presbycusis and progress with age (Sergeyenko et al, 2013; Möhrle et al, 2016). The protection of IHC and OHC function and therapeutic counteraction of noiseinduced or age-dependent hearing loss may be vital for maintaining speech comprehension and for the preservation of central auditory, or even cognitive, functions (Livingston et al, 2017). There is an urgent need for new pharmacological prevention strategies that have the potential to preserve cochlear hair cells and auditory fibers during aging and in response to the daily noise burden
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