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Abstract
PURPOSE: An ocular renin-angiotensin system has been implicated in the proliferation of retinal blood vessels and blindness in diabetes mellitus. Its cellular basis has not been established. The objective was to identify sites of renin synthesis, secretion, and processing in eyes from humans, BALB/c mice, Sprague-Dawley rats, and a hypertensive transgenic rat model (mREN-2) that displays amplified extrarenal renin synthesis. METHODS: Paraffin sections of eyes were incubated with antisera to renin protein, prorenin, vimentin, and Müller cells. Enzyme kinetic renin assay was performed on extracts of whole eyes (excluding lens and vitreous) and comparisons made with adrenal glands and kidneys. For detection of renin mRNA, retinas were separately pooled from BALB/c and Swiss mice. RESULTS: In normal rodent and autopsy human eyes, labeling for renin, vimentin, and Müller cell protein was observed in the cytoplasm of all macroglial Müller cells, with renin labeling most obvious in endfeet closely apposed to retinal blood vessels. Prorenin labeling was not detected. Less intense renin labeling, again without prorenin, was seen in nonpigmented ciliary epithelium of rodents. In transgenic (mREN-2) rat eyes, renin and prorenin labeling of Müller cells and nonpigmented ciliary epithelium were intense. Prorenin was localized to the posterior region of Müller cells but only sparsely to endfeet in rodent retinas, and renin was present only in an active form in amounts one third that of one adrenal. Renin mRNA was readily detected. In human retina, renin was present in active and pro-forms, and the total amount was approximately one fiftieth that of adrenal. CONCLUSION: Renin is synthesized in the retina and is specifically localized to the macroglial Müller cells. Nonpigmented ciliary epithelium also contains renin. The presence of prorenin in the posterior part of the Müller cell, with active renin throughout but notably in endfeet in apposition to retinal capillaries, suggests directional processing of renin. These findings are consistent with earlier suggestions that retinal neovascularization may be associated with Müller cell dysfunction.