Abstract-Unlike the ubiquitous angiotensin-converting enzyme (ACE), the ACE-related carboxypeptidase 2 (ACE 2) is predominantly expressed in the heart, kidney, and testis. ACE 2 degrades angiotensin (Ang) II to Ang (1-7) and Ang I to Ang (1-9). We investigated the expression of ACE and ACE 2 in a rodent model of type 2 diabetes. ACE and ACE 2 were measured in kidney and heart from 8-week-old no diabetic control (db/m) mice and diabetic (db/db) mice, which at this young age have obesity and hyperglycemia without nephropathy. Key Words: angiotensin-converting enzyme Ⅲ renin-angiotensin system Ⅲ diabetic nephropathy Ⅲ obesity Ⅲ mice Ⅲ ACE-related carboxypeptidase 2 A lterations within the renin-angiotensin system (RAS) are considered to be pivotal for the development of diabetic complications, particularly diabetic renal disease and hypertension. 1-4 The angiotensin-converting enzyme (ACE), a key element of RAS, is primarily a membrane-bound protein residing on the surface of epithelial and endothelial cells. 5 Through its 2 catalytic domains, ACE cleaves the inactive precursor angiotensin (Ang) I to Ang II, which induces vasoconstriction, aldosterone release, and acts as growth modulator. [5][6][7] Most tissue beds, including the kidney, express a local RAS that acts independently of the circulating system. [7][8][9] There is also a growing body of evidence that implicates the more recently characterized peptides Ang (1-7) and Ang (3-8) as additional bioactive components of the RAS. 10 -12 Recently, a homologue of ACE, an ACE-related carboxypeptidase (ACE 2), has been identified in humans and rodents. [13][14][15] It contains only a single enzymatic site that is capable of catalyzing Ang I to Ang (1-9). It also degrades Ang II to the vasodilator Ang (1-7) and this may counterbalance the Ang II-forming activity of ACE. 15,16 In contrast to ACE, ACE 2 activity is not inhibited by ACE inhibitors. 13 Previous studies using the streptozocin (STZ) model of diabetes revealed decreased renal expression of ACE. [17][18][19] A recent study using this rat diabetic model showed a reduction in ACE 2 as well. 18 These previous studies involved diabetic rats with advanced renal lesions. [17][18][19] The aim of the present study was to characterize the expression of ACE and ACE 2 in kidney from diabetic mice (db/db) before the development of nephropathy. The db/db mouse is a genetic model of type 2 diabetes caused by an inactivating mutation of the leptin receptor gene that results in a shorter intracellular domain of the receptor and a failure to transduce signals. 20,21 As a result of this mutation, hyperglycemia develops in association with insulin resistance and obesity at Ϸ4 to 7 weeks after birth. 22 The db/db mouse eventually has some, but not all, features of

Chronic kidney disease has the potential to induce sequelae that can have severe and mortal outcomes. In particular, impaired glomerular filtration can cause a hyperphosphatemic state, which, if left unchecked, can lead to secondary hyperparathyroidism, vascular calcification, and renal osteodystrophy. Therapeutic management of hyperphosphatemia must maintain both phosphorus and calcium serum concentrations within the recommended guidelines. The balance of both minerals is regulated by parathyroid hormone; thus, an imbalance of one affects the other. In end-stage renal disease, patients often present with hypocalcemic levels due to the kidneys' inability to generate active vitamin D to promote calcium absorption in the intestine. Absorption of calcium can be increased by the administration of active vitamin D analogues. Minimizing phosphorus intake through a strict dietary regimen, combined with the use of phosphate binders to absorb excess ingested phosphate, can help to maintain serum phosphate levels near the recommended concentration of 5.5 mg/dL. Phosphate-binding compounds have evolved from the original aluminum-based binders pioneered in the 1970s to calcium-based binders such as calcium acetate, and more recently, to the following additions to the nephrologist's armamentarium: sevelamer--a polyhydrochloride polymer, and lanthanum carbonate. One of the top 2 common clinical treatments for hyperphosphatemia, calcium acetate, has an established history of efficacy since the 1980s, and has been shown to be cost effective and well tolerated, as well.

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