Diabetic nephropathy (DN) is one of the most common and severe microvascular complications of diabetes mellitus (DM), significantly contributing to increased mortality in patients with DM. Chronic Kidney Disease occurring among people with diabetes is considered common, morbid, and costly (1). The International Diabetes Federation estimates that 537 million people were living with diabetes in 2021, with an expected increase to 784 million by the year 2045 (2). As the prevalence of diabetes has increased, the prevalence of DN has grown proportionally (3). The prevalence of CKD among people with diabetes is >25%, and it has been estimated that 40% of people with diabetes develop CKD during their lifetime (3).

To date, several key mechanisms are known to explain the development and progression of DN, including oxidative stress, angiotensin II (Ang-II), and inflammatory processes (4). Investigating the role of inflammatory mechanisms in the development and progression of DN not only enhances our understanding but also identifies novel therapeutic targets for the development of anti-inflammatory therapeutic strategies (4).

Patients with VD deficiency are at an increased risk for developing DN. Recent basic and clinical studies have demonstrated that VD and its analogs exhibit kidney protective effects, such as anti-proteinuria, antifibrosis, anti-inflammatory, and prevention of podocyte damage by binding to the vitamin D receptor (VDR). However, the specific mechanisms by which VD and VDR influence various pathological processes in DN remain unclear. This review aimed to summarize the current research on the role of the VD/VDR signaling pathway in DN and explore the clinical therapeutic potential of VD and VDRAs in renoprotective processes.

VD is a fat-soluble prohormone crucial for calcium and bone metabolism. In addition, VD affects various tissues of the body, including the kidneys. The two primary sources of VD are diet (20%) and skin exposure to sunlight (80%), the latter initiating the synthesis of several VD-related cascades in the body. VD undergoes two hydroxylation processes to become its active form: the first process occurs in the liver, converting VD to 25(OH) D3, and the second process takes place in the kidneys, resulting in 1, 25-dihydroxyvitamin D [1,25(OH) 2D3]—also known as calcitriol. The renal production of 1,25 (OH)2D3 in the body is normally regulated by the levels of parathyroid hormone (PTH) in the plasma and the levels of calcium and phosphorus in the serum. VD is transported in the bloodstream by binding to VD-binding protein (VDBP). VD deficiency has reached epidemic proportions globally and is associated with several health problems, including defects in bone mineralization (such as osteoporosis and osteomalacia), an increased risk of DM (5), immune defects (6), and cardiovascular disease (7).

Several studies have found that VD levels are lower in patients with DN. According to the Endocrine Society, VD deficiency is defined as a 25(OH)D3 level of less than 20 ng/mL (50 nmol/L) (8). The uptake and activation of VD depends on the formation of the VDBP/25(OH) D3 complex, its filtration, and subsequent reabsorption in the renal proximal tubular cells. In DN, studies have shown increased urinary elimination of VDBP, leading to elevated concentrations of VDBP in the urine (9). The biological effects of VD are mediated through the VDR, which is present in a variety of tissues and cells, such as the intestines, bones, parathyroid glands, reproductive system (10), and kidneys (11, 12).

The interaction between VD and VDR in these diverse tissues explains the broad range of symptoms and signs that can arise from VD deficiency. Numerous studies suggest that the VD/VDR axis is linked to the development of various diseases.

In the kidneys, VD with VDR specifically target proximal and distal tubular epithelial cells, glomerular parietal epithelium, collecting duct cells, mesangial cells, podocytes, and the juxtaglomerular apparatus (10, 13). As is well established, the kidneys play a crucial role in VD metabolism by regulating the reabsorption of calcium and phosphate and controlling the synthesis of its active form. The multiple effects of the VD/VDR signaling pathway include the maintenance of mineral homeostasis, the regulation of inflammation and immune responses, and potential therapeutic effects in cancer (14, 15).

In the kidneys, VD plays a crucial role in maintaining podocyte health, preventing epithelial-to- mesenchymal transition (EMT), preventing inflammation, and suppressing the expression of the renin gene by regulating the renin-angiotensin-aldosterone system (RAAS) (16). DN, also referred to as a diabetic kidney disease (DKD), is characterized by increased urinary albumin excretion, decreased glomerular filtration rate (GFR), or both (2). Approximately 40% of patients with DM who develop DN, are at risk of progressing to end-stage renal disease (ESRD) and an increased risk of developing cardiovascular diseases (17, 18).

DN is a serious problem that unfavorably affects human health. Mounting evidence from animal and clinical studies has suggested that VDRAs has beneficial effects on various renal diseases including DN mainly by reducing albuminuria.

Hyperglycemia is the primary driver of intracellular metabolism dysregulation, inflammation, enhanced cell apoptosis, and tissue fibrosis (19). High glucose induces oxidative and nitrosative stress in many cell types causing the generation of species such as superoxide, nitric oxide and peroxynitrite and their derivatives. Herby, the role of these species in high glucose-mediated apoptotic cell death is relevant to the complications of diabetes such as neuropathy, nephropathy and cardiovascular disease. Hyperglycemia causes activation of several proteins involved in apoptotic cell death, including members of the caspase and Bcl-2 families (20).

The role of VD in the pathogenesis of DN is multifaceted, particularly in terms of podocyte injury, RAAS alteration, inflammatory responses, and insulin resistance, as discussed below and illustrated in the Figure 1 .

Many efforts have been made to standardize the treatment of patients with DN, with a primary focus on halting the progression of DN. New therapies targeting oxidative stress and inflammation have sparked significant research interest. In managing DN, first of all, maintaining glycemic control is crucial, and the American Diabetic Association recommends an HbA1c level of 7% (39).

With regard to the antidiabetic therapies recommended for DN and maintaining glucoregulation without damaging the kidneys, incretin-related drugs (such as dipeptidyl peptidase 4 inhibiators-DPP4i and glucagon like peptide 1 receptor agonist-GLP-1 RA) are commonly used for glycemic control. Other promising therapies include mineralocorticoid receptor antagonists, endothelin receptor antagonists, and therapies targeting inflammation and free radicals.

Additionally, resveratrol and Nrf2 are gaining attention for DN management. Notably, there is significant interest in VDRAs (paricalcitol and calcitriol). These agents help control proteinuria and have a significant role in blocking the RAAS (40). The renoprotective effect of VDRAs involves the inhibition of podocyte apoptosis and protects against podocyte damage (41). Furthermore, calcitriol has been shown to reduce the levels of fibroblast growth factor 23 (FGF23), which is a risk factor for the development of DN and can contribute to podocyte edema (42). Paricalcitol, a third-generation VD analog widely used to prevent and treat DN, is often used to replace active VD concentrations and provides a negative feedback stimulus to the parathyroid gland, reducing the secretion of PTH. Paricalcitol is preferred over calcitriol as it results in fewer episodes of hypophosphatemia and hypercalcemia (43). In a large-scale RCT (VITAL study), treatment with 2 μg of paricalcitol for 24 weeks in patients with both type 2 DM and DN led to a reduction in residual albuminuria excretion (44). Numerous studies have also confirmed the renoprotective effects of paricalcitol and its ability to reduce albuminuria in patients with DM (45, 46).

Many other RCT and well-designed observational studies have reported the recovery of renal function after VD therapy in patients with DN where except albuminuria reduction, it was also found increased eGFR growth and decreased serum creatinine (48, 49, 51, 53, 54) while some other RCT except albuminuria reduction have reported no significant differences in serum creatinine and eGFR (53). A few studies have shown controversies with no statistically significant benefit of vitamin D therapy on renal function (50, 52). Please refer to Table 1 for main findings from clinical studies of VD and VDRA on DN (studies with synergical drug combination were not considered in analyses) and Table 2 for different forms of VD medications used in the treatment of DN.

A systematic review and meta-analysis assessed the effects of VD supplements on renal function, inflammation, and glycemic control in patients with DN. The analysis showed that VD supplements, including calcitriol, alfacalcidol, and 1,25(OH)2D3, are beneficial in reducing the levels of 24-hour urine protein and inflammation markers, such as high-sensitivity C-reactive protein (hs-CRP). However, these supplements have no significant effects on hemoglobin A1c, serum creatinine, estimated GFR, and glycemic control indices in patients with DN (47).

Krairittichai et al., in their open-label RCT, revealed that percent changes in urine protein creatinine ratio (UPCR) from baseline to the last evaluation in the calcitriol (0.5 ug twice weekly) for 16 weeks and control groups were -18.7% and + 9.9% (p < 0.01) respectively (48). In another double-blind RCT, patients with DN were administered 50,000 UI per month of intramuscular calcitriol for 6 months, resulting in a significant reduction in urinary albumin creatinine ratio (49).

Animal and clinical studies have demonstrated that VD and VDRA not only regulate calcium and phosphorus levels they also improve the clinical outcomes of DN. Their benefits include reducing proteinuria, exerting anti-fibrotic and anti-inflammatory effects, and preventing podocyte damages. These properties make VD and VDRA promising options for the prevention and treatment of DN. However, long-term followed-up, RCT of larger sample size, placebo controlled comprehensive outcome measure, are necessary to comprehensively evaluate the effect of VDRA on DN, in order to clarify the real impact of VD on DN including their impact on proteinuria, renal function, progression to ESRD, morbidity, and mortality.