Diabetic Nephropathy (DN) is one of the most important complications of type 2 diabetes mellitus (T2DM) and is the most common cause of end stage renal disease (ESRD). DN patients have a progressive renal failure that highly correlates with proteinuria. So, a decrease in urinary protein excretion is effective in protecting the renal function and delaying the progression of DN.

Vitamin D is an essential hormone in the body and its major role is to regulate calcium and phosphorus metabolism in the body. Epidemiological data indicate that patients with diabetic nephropathy are more likely to suffer from vitamin D deficiency [1]. Vitamin D deficiency is very common and may play an important role in the occurrence and development of diabetic nephropathy [2]. Recently, an ever growing number of studies have shown that vitamin D plays a role in renal protection [3,4]. There have been many randomized controlled trials (RCTs) on the effect of vitamin D supplementation on proteinuria in DN patients [5-13]. And one previous meta-analysis [14] showed vitamin D supplementation could provide beneficial effects on 24-hour urine protein and inflammation indexes in DN patients. But the mechanisms of vitamin D and vitamin D receptor (VDR) in different pathological processes in DN are still unclear. This review summarizes the currently important and novel research on the roles and mechanisms in DN, in order to further study the multiple and crucial roles of vitamin D.

Vitamin D is a kind of steroid hormone with active form 1,25(OH)2D3 which is also called calcitriol. Vitamin D has been known for its important role in regulating blood calcium and blood phosphorus concentrations. Human beings can produce vitamin D from 7-dehydrocholesterol in the skin by the effect of ultraviolet rays (10 nm-400 nm). Little vitamin D can be absorbed from foods such as fatty fish. Vitamin D is converted to 25-hydroxyvitamin D (25OH-D) by the influence of 25-hydroxylase in the liver, subsequently turned into the active form 1,25(OH)2D3 by 1α-hydroxylase (mainly CYP27B1) in human renal proximal tubular epithelial cells (PTECs). The binding of 1,25(OH)2D3 to the vitamin D receptor (VDR) in the nuclear receptor affects gene transcription. In general, 1,25(OH)2D promotes dietary calcium and phosphorus absorption in the intestine and regulates reabsorption of calcium in the renal tubules. Because VDR is expressed in a variety of organs, such as the heart, liver, blood vessels, and the central nervous system, 25-hydroxyvitamin D-1α-hydroxylase is also expressed in these tissues.

Vitamin D has long been used to regulate calcium homeostasis and bone metabolism in CRF patients and maintenance hemodialysis (MHD) patients. Recent studies suggest that it could ameliorate proteinuria and delay progression of renal damage in DN patients [15]. However, other studies did not find potential benefit of active vitamin D supplementation on urinary protein excretion in DN patients [16]. Considering the controversy, a meta-analysis is conducted to evaluate the effect of active vitamin D preparation on UACR and UAER in DN patients. The results support the current evidence for a clinical benefit of active vitamin D to reduce urinary albumin excretion in DN patients. The mechanism of anti-proteinuric effect of vitamin D is multifaceted.

The mechanism of vitamin D in renin-angiotensin-aldosterone system (RAAS)

RAAS plays a critical role in the development of DN. Vitamin D may play a renoprotective role in DN by negative regulation of RAAS by suppressing renin expression. An increased renin and angiotensin II concentration in plasma was detected in VDR-null mice compared with wild-type mice. Following unilateral ureteral obstruction in VDR-null mice, there was an upregulation of extracellular matrix proteins and profibrogenic and proinflammatory factors such as MCP-1 and TGF-β. Vitamin D is a negative regulator of RAAS. Vitamin D can also inhibit the production of cytokines such as transforming growth factor-β (TGF-β) and monocyte chemottractant protein-1 (MCP-1) [17], which are pivotal in the progression of glomerulosclerosis.

The mechanism of vitamin D in insulin resistance

Insulin resistance is not only an important cause of type 2 diabetes mellitus (T2DM), but also the basis for renal injury in T2DM patients. Recent research suggested vitamin D could alleviate insulin resistance [18,19]. The mechanism might be that it can promote the expression of insulin receptor. One study found that there are vitamin D receptors in islet beta cells, and the polymorphism of vitamin D receptor genes (TaqI?BsmI?ApaI?FokI) is closely related to insulin resistance [20].

The mechanism of vitamin D in abnormal lipid metabolism

Abnormal lipid metabolism is an independent risk factor of DN. Lipid deposition promotes proliferation of mesangial cell and production of extracellular matrix. Lee et al. [21] confirmed that vitamin D inhibits the expression of peroxisome proliferator-activated receptor (PPARs) and the differentiation of 3T3-L1 preadipocytes to adipocytes. Other studies [22] have shown that it could lower blood lipids by increasing apolipoprotein A1 and high density lipoprotein cholesterol (HDL-c).

The mechanism of vitamin D in podocyte injury

Podocytes, the outermost layer of glomerular filtration, are highly differentiated epithelial cells in the glomerular basement membrane playing a key role in the regulation of glomerular filtration in the kidney. The foot processes are a vital part of the glomerular filtering barrier, preventing proteins and other macromolecules from being filtered into the urine. In the causes of kidney damage, podocytes serve as the last gate of the glomerular filtration barrier, and their damage will lead to occurrence of proteinuria, which will further increase kidney damage. DN is considered one kind of podocyte disease. According to some reports, 1,25(OH)2D3 could promote the expression of nephrin which are key components of the slit diaphragm formed between adjacent crossed foot processes. As the main size and charge-selective barrier of proteins, podocyte injury will lead to proteinuria and worsen DN and eventually develop into ESRD. Reducting urinary albumin excretion through any intervention leads to a reduced incidence of these outcomes.

The mechanism of vitamin D in interstitial fibrosis

Studies have found that the expression of VDR in renal tissue was significantly decreased in the mice suffering from renal interstitial fibrosis, which indicated the importance of VDR. The downregulation of VDR could be rescued by treating one kind of active vitamin analog paricalcitol. In addition, the therapeutic effect of paricalcitol on renal interstitial fibrosis has also been significantly associated with its regulation effect on VDR expression. There are many reports demonstrating that 1,25(OH)2D3 combined with VDR could inhibit the progression of DN fibrosis by inhibiting the production of FN and the activation of TGF-β and RAAS in high glucose-treated mesangial cells [23]. It can also directly block TGF-β-induced EMT and extracellular matrix (ECM) proteins in cultured tubular via antagonizing NF-κB activity. What is more, 1,25(OH)2D3 can improve renal fibrosis via reducing the expression of collagen, other key profibrotic factors, and increasing the expression of antifibrotic factors, such as BMP7 and MMP8. VDR also directly inhibits the expression of Snail and stimulates E-cadherin expression in primary tubular cell cultures as a means of EMT prevention. In conclusion, these researches affirmed the protective role of VDR in inhibiting renal fibrosis. Furthermore, there are studies that have demonstrated the effect of vitamin D on decreasing the progression of renal fibrosis, by inhibiting insulin-like growth factor-1 (IGF-1) and ameliorating podocyte injury, through the nephrin signaling pathway [24,25].

The mechanism of vitamin D in micro-inflammation

Micro-inflammation is also crucial in the progression of DN, which eventually leads to renal fibrosis. Increased inflammation is regarded as a hallmark of diabetes and plays a key role in the development and progression of DN. Expression of proinflammatory cytokines, chemokines, and cell adhesion molecules is increased in the serum and urine of patients with diabetes and DN. Reducing inflammatory processes can either alleviate or prevent the development of kidney damage in animal models of DN. Recent studies have shown that VDR agonists can effectively alleviate the progression of DN by reducing renal inflammation in DN. Inflammation is involved in the pathogenesis of DN through various proinflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-18 (IL-18), monocyte chemoattractant protein-1(MCP-1), and tumor necrosis factor-α (TNF-α). Moreover, transcription factor NF-κB is an important inflammatory stimulus for DN, which regulates adhesion molecule gene expression chemokines and cytokines. Emerging evidences have showed that VDR activation plays an anti-inflammatory role by inhibiting the activation of NF-κB in tubular and mesangial cells. Previous studies demonstrated that vitamin D has anti-inflammatory and immunomodulatory effects [26], and it plays a renal protective role by improving the local micro-inflammatory state of the kidney [27,28]. Previous meta-analysis [29] also found that vitamin D could reduce levels of key inflammatory factors, including hs-CRP, TNF and IL-6 in DN patients, which was consistent with other studies.

It is now well recognized that vitamin D plays an important role not only in regulating blood calcium and phosphorus levels but also in the progression of many other diseases such as kidney diseases, especially in DN. Current evidence suggested a clinical benefit of active vitamin D to reduce urinary albumin excretion in DN patients. We consider that vitamin D has shown an increasingly important protective role in DN through multiple mechanisms of action.