Calcitriol regulates angiotensin-converting enzyme and angiotensin converting-enzyme 2 in diabetic kidney disease

Abstract

To investigate the effects of calcitriol on angiotensin-converting enzyme (ACE) and ACE2 in diabetic nephropathy. Streptozotocin (STZ) induced diabetic rats were treated with calcitriol for 16 weeks. ACE/ACE2 and mitogen activated protein kinase (MAPK) enzymes were measured in the kidneys of diabetic rats and rat renal tubular epithelial cells exposed to high glucose. Calcitriol reduced proteinuria in diabetic rats without affecting calcium-phosphorus metabolism. ACE and ACE2 levels were significantly elevated in diabetic rats compared to those in control rats. The increase in ACE levels was greater than that of ACE2, leading to an elevated ACE/ACE2 ratio. Calcitriol reduced ACE levels and ACE/ACE2 ratio and increased ACE2 levels in diabetic rats. Similarly, high glucose up-regulated ACE expression in NRK-52E cells, which was blocked by the p38 MAPK inhibitor SB203580, but not the extracellular signal-regulated kinase (ERK) inhibitor FR180204 or the c-Jun N-terminal kinase (JNK) inhibitor SP600125. High glucose down-regulated ACE2 expression, which was blocked by FR180204, but not SB203580 or SP600125. Incubation of cells with calcitriol significantly inhibited p38 MAPK and ERK phosphorylation, but not JNK phosphorylation, and effectively attenuated ACE up-regulation and ACE2 down-regulation in high glucose conditions. The renoprotective effects of calcitriol in diabetic nephropathy were related to the regulation of tubular levels of ACE and ACE2, possibly by p38 MAPK or ERK, but not JNK pathways.

A brief review of interplay between vitamin D and angiotensin‐converting enzyme 2: Implications for a potential treatment for COVID‐19

“…Furthermore, clinical features and pathological changes of lung tissues in the calcitriol‐treated LPS rats were remarkably milder than controls 67 . Lin et al 68 observed that calcitriol decreased ACE concentration and ACE/ACE2 ratio and enhanced ACE2 concentration in diabetic rats. In addition, calcitriol treatment remarkably suppressed p38 mitogen‐activated protein kinase and extracellular signal‐regulated kinase (ERK) phosphorylation, but not c‐Jun N‐terminal kinases phosphorylation, and effectively weakened ACE up‐regulation and ACE2 down‐regulation 68 .…”

Intrarenal Angiotensin-Converting Enzyme: the Old and the New

“…The AT1R antagonist candesartan, a well-accepted therapy in diabetic nephropathy, has recently been shown to improve renal tubular damage and albuminuria, partially through upregulation of ACE2/AT2R/Mas axis activity in the kidney [27•]. Conversely, treatment of diabetic rats with calcitriol reduced renal ACE levels and increased renal ACE2 expression, thus decreasing the ACE/ACE2 ratio, and associated with a reduction in proteinuria [54•]. Interestingly, in this study, reductions in ACE were mediated by the p38MAPK pathway, while ACE2 was upregulated via the ERK signaling pathway [54•].…”

“…Conversely, treatment of diabetic rats with calcitriol reduced renal ACE levels and increased renal ACE2 expression, thus decreasing the ACE/ACE2 ratio, and associated with a reduction in proteinuria [54•]. Interestingly, in this study, reductions in ACE were mediated by the p38MAPK pathway, while ACE2 was upregulated via the ERK signaling pathway [54•]. Systemic use of recombinant human ACE2 in diabetic mice similarly attenuated kidney injury while reducing blood pressure and decreasing NADPH oxidative activity [55].…”

Vitamin D Actions on Cell Differentiation, Proliferation and Inflammation

“…1,25-(OH) 2 D 3 acts as a negative regulator of renin gene expression via cAMP response element-binding protein (CREB) inhibition, which is required for the expression of renin [21]. In an experimental model of diabetic nephropathy, it was demonstrated that 1,25-(OH) 2 D 3 also has a suppressive effect on the expression of angiotensin converting enzyme 1 and 2(ACE), demonstrating the renoprotective action of in 1,25-(OH) 2 D 3 on the modulation of RAS [22]. The effects of the host 25(OH)D levels could extend beyond the macrophage, as lung epithelial cells have been demonstrated to express 1α-hydroxylase, and convert 25(OH)D into 1,25(OH) 2 D 3 leading to expression of cathelicidin [23].…”