Mineralocorticoid receptor mediates glucocorticoid treatment effects in the autoimmune mouse ear.
The standard treatment for many hearing disorders is glucocorticoid therapy, although the cochlear mechanisms involved in steroid-responsive hearing loss are poorly understood. Cochlear dysfunction in autoimmune mice has recently been shown to be controlled with the mineralocorticoid aldosterone as effectively as with the glucocorticoid prednisolone. Because aldosterone regulates sodium, potassium, and other electrolyte homeostasis, this implied the restoration of hearing with the mineralocorticoid was due to its impact on cochlear ion transport, particularly in the stria vascularis. This also suggested glucocorticoids may be controlling hearing recovery in part through their binding to the mineralocorticoid receptor in addition to their glucocorticoid receptor-mediated anti-inflammatory and immunosuppressive functions. Therefore, the aim of the present study was to better delineate the role of the mineralocorticoid receptor in steroid control of hearing in the autoimmune mouse. Spironolactone, a mineralocorticoid receptor antagonist, was administered to MRL/MpJ-Fas(lpr) autoimmune mice in combination with either aldosterone or prednisolone to compare their hearing and systemic disease with mice that received either steroid alone. ABR thresholds showed either aldosterone or prednisolone alone preserved hearing in the mice, but spironolactone prevented both steroids from maintaining normal cochlear function. This suggested both steroids are preserving hearing through the mineralocorticoid receptor within the ear to regulate endolymph homeostasis. The spironolactone treatment did not block normal glucocorticoid receptor-mediated immune-suppression functions because mice receiving prednisolone, either with or without spironolactone, maintained normal body weights, hematocrits, and serum immune complexes. Thus, reducing systemic autoimmune disease was not sufficient to control hearing if mineralocorticoid receptor-mediated functions were blocked. It was concluded the inner ear mineralocorticoid receptor is a significant target of glucocorticoids and a factor that should be considered in therapeutic treatments for steroid-responsive hearing loss.
Trune
Dennis R
DR
Oregon Hearing Research Center, Department of Otolaryngology-Head and Neck Surgery; Oregon Health and Science University, Mail Code NRC04, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098, USA. truned@ohsu.edu
Kempton
J Beth
JB
Gross
Neil D
ND
D000450:Aldosterone / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000936:Antigen-Antibody Complex / Q000187:drug effects; D001309:Auditory Threshold / Q000187:drug effects*; D001327:Autoimmune Diseases / Q000188:drug therapy*; D001835:Body Weight / Q000187:drug effects; D003051:Cochlea / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use*; D006319:Hearing Loss, Sensorineural / Q000188:drug therapy*; D006400:Hematocrit; D051379:Mice; D000451:Mineralocorticoid Receptor Antagonists; D011239:Prednisolone / Q000494:pharmacology / Q000627:therapeutic use; D011897:Random Allocation; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D013148:Spironolactone / Q000494:pharmacology / Q000627:therapeutic use
D000936:Antigen-Antibody Complex; D005938:Glucocorticoids; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000450:Aldosterone; D011239:Prednisolone