Renin-1 Is Essential for Normal Renal Juxtaglomerular Cell Granulation and Macula Densa Morphology

Abstract

The secretion of renin from granules stored in renal juxtaglomerular cells plays a key role in blood pressure homeostasis. The synthesis and release of renin and the extent of granulation is regulated by several mechanisms including signaling from the macula densa, neuronal input, and blood pressure. Through the use of a gene-targeting vector containing homology arms generated using the polymerase chain reaction, we have inactivated the Ren-1 d gene, one of two mouse genes encoding renin, and report that lack of renin-1 d results in altered morphology of the macula densa of the kidney distal tubule and complete absence of juxtaglomerular cell granulation. Furthermore, Ren-1 d؊/؊ mice exhibit sexually dimorphic hypotension. The altered growth morphology of the macula densa in Ren-1 d -null mice should provide a tool for the investigation of the JG cell-macula densa signaling. Furthermore, the current data indicate that expression of the Ren-1 d gene is a prerequisite for the formation of storage granules, even though the related protein renin-2 is present in these mice, suggesting that renin-1 d and renin-2 are secreted by distinct pathways in vivo.Renin (EC 3.4.23.15) is an aspartyl protease, which catalyzes the first step in the renin angiotensin system, the end product of which is the potent vasopressor peptide hormone, angiotensin II (AngII).1 This octapeptide acts to increase peripheral vascular resistance and promote salt and fluid retention in concert with the hormone aldosterone. Renin is synthesized principally in the kidney juxtaglomerular (JG) cells, a group of modified smooth muscle cells located at the distal end of the renal afferent arteriole of the glomerulus (1). JG cells are in close contact with the macula densa, a specialized plaque of epithelial cells of the kidney distal tubule, which signal to the renal arterioles to regulate glomerular filtration rate and the secretion of renin, in response to ionic concentration and flow rate in the distal tubule (2, 3), the so-called tubuloglomerular feedback loop. Except for the submandibular gland (SMG) of the mouse, the JG cells are the only site where prorenin, the inactive zymogen, is known to be converted to the active form of renin. SMG renin does not, however, make its way into the plasma in large quantities and is thought not to play a significant role in blood pressure regulation under normal circumstances (reviewed in Bing et al. (4)). The release of renin from JG cells is mediated by two pathways: regulated release of the mature, active renin from modified lysosomal storage granules and constitutive release of the inactive zymogen. While the regulated pathway of renin secretion is responsive to baroreceptor, neurogenic, and macula densa signals (5), the physiological significance of the constitutive secretion of prorenin is not understood, nor are the molecular pathways that link secretory signals to renin maturation and release. Clarification of the mechanisms underlying these processes will be crucial to our understanding of the control of ...

A genetically clamped renin transgene for the induction of hypertension

“…Developing a model in which the effector molecule renin is held at a constant level would be of great value. Because of the complex nature of the renin genes in the commonly used 129 mouse strain, it has been a challenge to generate mouse models that overexpress renin in a form that is active in mice or that delete both renin genes (3,35,36). In this paper, we have used single-copy chosen-site gene targeting to generate a mouse line that produces genetically clamped high levels of mouse active renin in the liver.…”

Cardiovascular and Renal Phenotype in Mice With One or Two Renin Genes

“…Both Ren-1 and Ren-2 are found in the kidney, 5 though Ren-2 also exists at some nonrenal sites. 9,10 Mice lacking a functional Ren-1 d gene have no JG-cell granulation and exhibit atypical macula densa morphology, 5,11 whereas blood pressure in females is lower (though it is similar in males).…”

“…Both Ren-1 and Ren-2 are found in the kidney, 5 though Ren-2 also exists at some nonrenal sites. 9,10 Mice lacking a functional Ren-1 d gene have no JG-cell granulation and exhibit atypical macula densa morphology, 5,11 whereas blood pressure in females is lower (though it is similar in males). 5 In the absence of Ren-1, plasma active renin is reduced, whereas inactive prorenin is increased, suggesting that Ren-1 d is a prerequisite for the formation of renin storage granules despite the presence of Ren-2-generated renin, and further that renin from Ren-1 and Ren-2 genes is secreted through different pathways.…”

“…4 Some strains have only the typical Ren-1 c gene, whereas others have two alternative genotypes at the renin locus, and thus two renin genes, designated Ren-1 d and Ren-2. 5 In these strains, the genes are tightly linked in tandem within chromosome 1, spanning over 40 kb.…”

“…9,10 Mice lacking a functional Ren-1 d gene have no JG-cell granulation and exhibit atypical macula densa morphology, 5,11 whereas blood pressure in females is lower (though it is similar in males). 5 In the absence of Ren-1, plasma active renin is reduced, whereas inactive prorenin is increased, suggesting that Ren-1 d is a prerequisite for the formation of renin storage granules despite the presence of Ren-2-generated renin, and further that renin from Ren-1 and Ren-2 genes is secreted through different pathways. Alternatively, Sharp et al 12 found that if they deleted the Ren-2 gene from Sv-129 mice by gene targeting, leaving only Ren-1 d , no morphological abnormalities or changes in blood pressure resulted, though active renin was increased and inactive prorenin was decreased.…”