The cardiac natriuretic peptides function as a hormonal mechanism to regulate body fluid and electrolyte balance, thereby maintaining normal blood volume and pressure ^[1][2][3][4][1,2,3,4]. Deficiency in atrial natriuretic peptide (ANP) causes salt-sensitive hypertension in mice [5]. Genetic variants in the human NPPA gene, encoding ANP, have been identified as key determinants in blood pressure levels in large populations ^[1][6][1,6]. More recent studies have implicated the natriuretic peptides in other physiological and pathological processes, such as cardiac potassium channel activity [7], vascular remodeling ^[8][9][8,9], inflammatory response ^{[10][11][12][13]}[10,11,12,13], and lipid metabolism ^[14][15][16][14,15,16].

The natriuretic peptides are synthesized as pre-pro-peptides. Post-translational modifications, including proteolytic processing and glycosylation, are important in regulating natriuretic peptide activities ^{[17][18][19][20][21]}[17,18,19,20,21]. Particularly, cleavage of the pro-fragment is essential for the activation of these peptides. Corin was cloned from the human heart as a novel serine protease that includes a transmembrane domain near the N-terminus and multiple modules in the extracellular region [22]. Such a protein modular arrangement resembles those in other type II transmembrane serine proteases, a group of trypsin-like enzymes involved in diverse biological processes ^[23][24][23,24]. Biochemical and genetic studies have shown that corin is the long-sought protease for ANP activation [20]. Corin also processes pro-brain or B-type natriuretic peptide (pro-BNP) in vitro ^[25][26][25,26]. Furin, however, likely plays a more important role in processing pro-BNP and pro-C-type natriuretic peptides (pro-CNP) ^[27][28][27,28].

2. Regulation of Sodium Homeostasis in Non-Cardiac Tissues

Sodium and body fluid homeostasis is crucial for normal blood pressure ^[29][38]. The heart is the major organ that produces ANP and BNP [2]. When blood volume and/or pressure increases, the heart releases the natriuretic peptides to enhance vasodilation in the peripheral tissue, and natriuresis and diuresis in the kidney. This cardiac endocrine function serves as a cardiorenal feedback mechanism to maintain normal blood volume and pressure ^[1][2][3][4][1,2,3,4]. Consistent with its role in processing cardiac natriuretic peptides, corin expression is most abundant in the heart [22]. The cardiac CORIN expression involves T-box transcription factor 5 (TBX5), GATA binding protein 4 (GATA4), and NK2 homeobox 5 (NKX2-5) transcription factors ^[30][31][32][39,40,41]. In single-cell RNA sequencing analyses, corin has been identified as an early surface marker that can be used to purify cardiomyocytes from human embryonic and induced pluripotent stem cells ^[32][33][41,42]. In corin knockout (KO) mice, ANP activation in the heart was undetectable ^[34][43], demonstrating the importance of corin in ANP generation. In non-cardiac tissues, including the kidney and skin, corin expression has been detected ^{[22][26][35][36]}[22,26,44,45]. Unlike secreted proteases, such as trypsin and prothrombin, corin is a transmembrane protein ^[22][37][22,46]. The single-span transmembrane domain at the N-terminus anchors corin onto the cell surface at the expression site. Based on this structural feature, corin is expected to function locally in the kidney and skin, as discussed below.

2.1. Renal Corin

2.1.1. Expression in Renal Epithelial Cells

Kidneys in mice, rats, and humans have been shown to express corin mRNA and protein ^{[22][26][38][39]}[22,26,47,48]. Similar renal expression has been reported for pro-ANP/ANP and the ANP receptor, natriuretic peptide receptor-A (NPR-A) ^[40][49]. Among renal segments, corin level is highest in the proximal tubules. The collecting ducts in the medulla express lower levels of corin, pro-ANP, and NPR-A. In contrast, little or no corin expression was detected in the glomerulus and the distal tubules ^[40][49]. The proximal tubules are important in renal reabsorption, a key physiological process in electrolyte, body fluid, and metabolic homeostasis ^[41][50]. The proximal tubule consists of a single layer of polarized epithelial cells connected by tight junctions. In experiments with confocal and electron microscopy, corin was found on the apical, but not basolateral, membrane in the polarized renal epithelial cells, which differs from the entire cell membrane distribution pattern in non-polarized cardiomyocytes ^[38][40][42][47,49,51]. The specific apical membrane expression probably indicates a function of corin on the lumen of the proximal tubules to inhibit sodium reabsorption, thereby promoting natriuresis. These findings also raise the question regarding the molecular mechanism underlying the apical corin expression in polarized epithelial cells. Specific apical distribution is one of the distinct features of polarized epithelial cells. Impaired protein trafficking to the apical membrane in renal epithelial cells has been associated with kidney disease ^[43][52]. Protein structural elements, including the transmembrane domain, N- and O-glycans, glycosyl-phosphatidylinositol anchor, and amino acid motifs, are known sorting signals in apical trafficking ^[44][53]. A recent study identified a novel DSSDE motif in low-density lipoprotein receptor-like repeat 8 (LDLR8) of corin as an apical sorting signal in polarized renal epithelial cells ^[42][51]. Amino acid substitutions in this motif abolished the specific apical corin trafficking in polarized Madin–Darby canine kidney (MDCK) cells ^[42][51]. LDLR-like repeats are protein modules found in many secreted and cell surface proteins ^[45][54]. The DSSDE motif is also present in other LDLR-containing cell surface receptors on the apical membrane in renal proximal tubules. CD320, for example, is a transcobalamin receptor for vitamin B12 uptake ^[46][47][55,56]. The N-terminal extracellular region of CD320 contains two LDLR domains, the second of which has a DSSDE motif. In polarized renal and intestinal epithelial cells, the DSSDE motif is required for specific apical trafficking of CD320 ^[42][48][51,57]. These findings indicate that the DSSDE motif in LDLR repeats may have a general role in apical trafficking in polarized epithelial cells. Additional studies have shown that the DSSDE motif-dependent apical trafficking of corin and CD320 is mediated by Rab11a ^[42][48][51,57], a member of the small GTPase superfamily, which plays a central role in apical trafficking in polarized epithelial cells ^[49][58]. Inhibition of Rab11a expression by a dominant negative Rab11a mutant or RAB11A gene knockdown abolished the specific apical targeting of corin and CD320 in MDCK and colon-derived Caco-2 cells ^[42][48][51,57]. Currently, it is unclear how Rab11a recognizes the DSSDE motif in corin and CD320 LDLR repeats. Further studies will be important to define the Rab11a-mediated mechanism, and to examine whether the DSSDE motif in other LDLR-containing proteins has a similar role in apical trafficking in polarized epithelial cells.

2.1.2. Functional Significance of Renal Corin Expression

Electrolyte homeostasis is imperative for survival in all animals. In primitive vertebrates in salty water, natriuretic peptides act as a key mechanism to excrete excessive salt ^[50][51][59,60]. Corin is conserved in all vertebrate species, ranging from fish to mammals, indicating the importance of corin function in physiological homeostasis. In corin-null mice, urinary sodium excretion was reduced, especially on high-salt diets ^[52][61]. Previously, ANP was shown to function in the inner medullary collecting ducts to inhibit sodium absorption ^[53][54][55][62,63,64]. In the kidney, however, most solutes in the glomerular filtrate are absorbed in the proximal tubules. The findings of high levels of corin, ANP, and NPR-A expression in the proximal tubules suggest a corin and ANP-mediated autocrine mechanism in this key renal segment to inhibit salt and water reabsorption. In agreement with a renal corin function in sodium homeostasis, increased renal corin levels have been observed in rats and humans on high-salt diets, possibly indicating a compensatory response to increase sodium excretion ^[56][65]. Another recent study in humans identified an association between CORIN variants and salt sensitivity, longitudinal blood pressure changes, and hypertension incidence ^[57][58][66,67]. In rat models of kidney injury and severe cardiorenal syndrome, low levels of renal corin were reported ^[38][59][47,68]. Similarly, low levels of renal corin were observed in patients with chronic kidney disease and sodium retention ^[39][48]. These findings indicate that impaired renal corin expression and/or function may be a pathological mechanism underlying sodium retention in kidney disease. Interestingly, cardiac and renal Corin gene expression responded differently in hypertensive rats treated with anti-hypertensive drugs ^[60][69]. Additional studies are needed to define the renal corin function, and to understand how cardiac and renal corin-mediated mechanisms are coordinated in regulating sodium and body fluid homeostasis. These studies may provide new insights into the pathogenesis of sodium and body fluid retention in patients with heart and kidney diseases.

2.2. Skin Corin

2.2.1. Eccrine Sweat Glands

Overheating can be life-threatening. Sweating is a basic skin function to lower body temperature, which is mediated primarily by eccrine sweat glands. Among mammals, humans have the highest number of eccrine sweat glands on the skin surface ^[61][70]. This anatomical feature provides an evolutionary advantage for humans to survive in hot environments. The original sweat produced in the eccrine glands is isotonic to plasma, with high levels of salt. Considerable amounts of salt are reabsorbed before sweat reaches the skin surface. This reabsorption process prevents salt loss and electrolyte imbalance, especially when large amounts of sweat is produced, for example, during hard labor or sports. To date, the molecular mechanisms controlling salt excretion and reabsorption in eccrine sweat glands are not completely understood ^[62][63][71,72]. Recently, corin, ANP, and NPR-A proteins were detected in the luminal epithelial cells in human and mouse eccrine sweat glands, indicating a potential function of corin and ANP in sweating ^[64][73]. Indeed, low levels of sweat and salt excretion were found in corin KO mice on normal- and high-salt diets, compared to those in wild-type (WT) mice ^[64][73]. When corin KO mice were treated with amiloride, an epithelial sodium channel (ENaC) inhibitor, sweat and salt excretion was normalized. Importantly, reduced sweat and salt excretion was not found in corin conditional KO mice, i.e., mice lacking only cardiac corin. These results indicate that corin-mediated ANP production and signaling in the skin promote sweat and salt excretion by inhibiting ENaC, which mediates sodium reabsorption in the eccrine sweat ducts ^[64][73]. Aldosterone is known to increase ENaC activity and sodium reabsorption in the eccrine sweat glands ^[65][74]. Corin-mediated ANP production and function counter the aldosterone function. In WT mice, aldosterone treatment decreased sweat excretion, whereas such an effect was not observed in corin KO mice ^[64][73]. These results suggest that in WT mice, aldosterone-promoted salt reabsorption and corin-activated ANP-promoted salt excretion were in balance, which was tilted, by exogenous aldosterone, in favor of salt reabsorption. In contrast, corin KO mice lack the anti-aldosterone function. As a result, endogenous aldosterone has reached the maximal effect, which could not be further enhanced by exogenous aldosterone ^[64][73]. These results show that corin and ANP act as an anti-aldosterone mechanism in the skin to promote sodium and sweat excretion.

2.2.2. Dermal Papilla and Coat Color in Animals

The dermal papilla is another site of corin expression. In mice of the Agouti background, corin deficiency renders a lighter coat color ^[36][45]. Genetic analyses indicate that corin is a suppressor of the agouti pathway in coat color specification, and that this function requires the protease activity of corin ^[36][66][45,75]. Consistently, Corin has been identified as one of the three major pigmentation genes in beach mice in the Gulf and Atlantic Coasts of the United States ^[67][76]. Similarly, a CORIN variant, causing H587Y substitution in the LDLR6 repeat of corin, was found to be a modifier of the dark coat stripes in tigers ^[68][77]. Biochemical studies indicate that corin suppresses the activity of Agouti signaling protein (ASIP), which inhibits melanocortin binding to melanocorin-1 receptor (MC1R) in the production of dark pigments ^[68][77]. Decreased corin activity increases ASIP function, thereby reducing the darkness of coat stripes in tigers ^[68][77]. These results are supported by a recent report, in which a CORIN variant, causing R795C substitution in the scavenger receptor domain, was associated with the golden (lighter) coat phenotype in Siberian tabby cats ^[69][78]. It will be interesting to determine whether corin plays a similar role in coat color specification in other mammalian species. In humans, corin is expressed in dermal stem and progenitor cells ^[70][71][72][79,80,81], and in hair follicles ^[64][73]. The significance of corin expression in human hair follicles remains unclear. There are no reports of CORIN variants associated with skin or hair color in humans. In chickens and sheep, CORIN is a genetic factor contributing to evolutionary adaptation in hot arid environments ^[73][74][82,83], probably reflecting the role of corin in promoting salt and water excretion ^[64][73]. Reduced corin activity is expected to increase salt and water retention, offering a survival advantage in hot arid environments. Consistently, a CORIN variant with reduced activity is found in individuals whose ancestry can be traced back to southern regions of the Sahara Desert ^[75][76][33,84]. In modern times, however, ample supply of water and dietary salt puts the individuals with the CORIN variant at a higher risk of developing hypertension and heart disease ^[75][77][33,85].