The major long term microvascular disorder of diabetes is DN. The current data revealed an obvious elevation in serum creatinine and urea levels in the renal disease groups compared to the healthy group. Also, FBS and HbA1c% recorded a marked higher levels in diabetic groups relative to healthy controls. Several researchers indicated that hyperglycemia and pro-inflammatory cytokines have a crucial role in the pathophysiology of DN. Notably, IL-1β is thought to enhance proliferation of mesangial cell, and matrix deposition  and plays a pivotal function in several diseases, including diabetes and atherosclerosis . Our study revealed that IL-1β level has been increased noticeably in all diabetic and renal disease groups and these finding was in parallel with Osborn et al.  who reported a correlation between the elevation in IL-1β levels with insulin secretion impairment, cell proliferation inhibition, and pancreatic β-cells apoptosis. Moreover, IL-1β-neutralizing antibody administration substantially decreases HBA1c% and enhances the role of islets in HFD-induced diabetic mice. Regarding the diabetic end-stage renal disease group, our results revealed a noticeable positive correlation between IL-1β with FBS and creatinine levels. These data were consistent with Lei et al.  who reported that IL-1β is esential to enhance the onset and development of diabetic renal disease, and is involved also in intraglomerular hemodynamics abnormalities . Additionally, Timoshenko et al.  revealed a significant role of IL-1β in murine model of crescentic glomerulonephritis where IL-1β has a significant impact on cellular effectors in glomeruli and glomerular injury mechanisms. Further, Palsamy and Subramanian  revealed that IL-1β with TNF-a may induce iNOS expression in glomerular mesangial cells, resulting in large amounts of NO production, leading to hyperfiltration and higher microalbuminuria. In this regard, IL-1β promotes progression of renal disease in chronic diabetic patients and could therefore be a potential therapeutic target for alleviate or delay DN.
In the pathogenesis of several inflammatory disorders, the role of IL-17 is well reported, but further studies are needed to explore its contribution in DN. In the present study, our finding observed a noticeable increase in serum IL-17 level in diabetic and renal groups relative to healthy controls. Chen et al.  mentioned that levels of serum IL-17 in newly diagnosed patients with T2DM have been markedly increased compared to healthy subjects. Also, several investigations showed that IL-17 had a central role in T2DM inflammation and complications . Interestingly, IL-17 activates the pathway of NF-κB  which induces pro-inflammatory cytokines expressions including, IL-1β, IL-6, TNF-α, and adhesion molecules, thereby initiate the destruction of several tissues . Moreover, IL-17 increases TNF-α up-regulation and chemokine (C-C motif) ligand-2 in tubular epithelial and mesangial cells, leading to recruit local macrophages . In diabetic mice, IL-17 mediates podocyte lesion, mesangial expansion, and kidney fibrosis in DN animal model . Moreover, activation of the IL-17A/NF-κB pathway may lead to diabetic renal inflammation. Among the diabetic end-stage renal disease group, our results showed a positive correlation between IL-17 with both HbA1c% and sodium concentration. Cytokines, including TGF-β1, TNF-α, Interferon-gamma, IL-17A, and IL-1β, can be control hypertension by influencing endothelial dysfunction, the equilibrium between water and salts, and sympathetic regulation . IL-17A could directly stimulate endothelial dysfunction-associated hypertension, as seen in transgenic mice overexpress IL-17A in keratinocytes  In IL-17A deficient mice, alterations in endothelium-dependent vasodilatation phenylephrine-induced contraction caused by AngII, and reactive oxygen species generation was inhibited [28,29]. However, sodium transporters and nephron expression and activities were modulated by IL-17A. Interestingly, IL-17A depletion has eliminated distal tubule transporter activation, in particular, the sodium-chloride co-transporter, the epithelial sodium channel, and decreased renal damage caused by AngII . By controlling activation, IL-17A significantly contributes to the etiopathogenesis of kidney fibrosis, T cell expression, and inflammatory-mediated cell infiltration . With modern clinical trials, the area of anti-IL-17A antibodies in treated different diseases has recently increased significantly. Thus, targeting the IL-17 pathway can reflect a novel therapeutic strategy in managing the progression of DN.
The relation of SNPs inside the IL-17 family's genes and a number of diseases was investigated recently, however, few studies have discussed their impact on kidney diseases. Kim et al.  recorded a marked correlation between the IL17RA rs4819554 A allele with end-stage renal disease patients. Besides, Coto et al.  reported a correlation between abnormal kidney function and SNP rs4819554 in the IL17RA promoter region. Regarding our knowledge, this is the first study to investigate the polymorphisms of IL-17 gene in the progression and development of DN. Our data showed a higher frequency of the heterozygous A/G polymorphism in diabetic groups, while non-diabetic renal dysfunction groups showed a higher frequency of homozygote G/G as compared to healthy controls. These findings suggest that the IL17 GG and AG genotype may be linked with the severity of the disease. Moreover, the molecular importance of IL-17A genotype with increased IL-17 production in persons with the A allele was supported by our results. Accordingly, Linhartova et al.  mentioned that variability of the IL-17A gene can partially affect T1DM management in diabetic patients.
Concerning IL-33, our results revealed a significant reduction in diabetic and renal disease groups relative to healthy controls. Duan et al.  mentioned that the expression of IL-33 has been markedly higher in patients without kidney damage. Among the diabetic chronic renal disease group, the current results exert a negative correlation between IL-33 with urea and sodium levels. Our findings were consistent with previous reports that explained the vital relation between IL-33 and the progression of renal diseases . Moreover, IL-2 and IL-33 together were protected against metabolic syndrome diseases, albuminuria, and polarize macrophages to alternatively activated macrophages (M2) phenotype . Recently, Stremska et al.  reported that IL-33 has a central role in facilitating Treg responses, therefore IL-33 and IL-2 may synergize to improve Tregs and can also protect against experimental acute kidney damage. On the contrary, Nile et al.  reported that IL-33 has been observed to be an endogenous "danger signal" or "alarm" for trigger the immune response for responding to hypersensitive disease, which indicate that IL-33 may act as a dual‑function. In addition, In diabetic nephropathy, the rise in IL-33 levels is not associated with kidney damage, but the elevation may a result of diabetes . Importantly, there is also a need to fully elucidate the processes underlining the association of IL-33 with diabetic renal disease.
In this study, it has been demonstrated that Bcl2 mRNA expression decreased in all diabetic and renal disease groups relative to the healthy group. Our results were in compatible with Cipollone et al.  who proved that Bcl2 expression has been substantially decreased in microalbuminuric diabetic patients as a result of elevation in oxidant load due to hyperglycemia. In addition, Bcl-2 downregulation leads to stimulation of the NF-kB route, thereby the progression of nephropathy. Almond and Cohen  reported that some Bcl2 family has been found to suppress apoptotic death by regulating the activation of caspases and mitochondrial membrane permeability . Notably, Bcl2 protein accumulation may occur via the signalling of mitogen-activated protein kinases and is a cause of intrinsic apoptotic events, with activation of apoptotic protease factor-1 and initiator caspase-9, accompanied by activation of -3 and -7 executioner caspases, cell death, and further renal injury . Concerning diabetic chronic kidney disease patients, the current findings exert a negative correlation between Bcl2 with creatinine and HBA1c%. These results have been consistent with the finding of Majewska et al.  who found a decrease in the expression of Bcl2 in end-stage renal disease patients compared to controls. This elevation of apoptosis may be a result of higher Bcl2-antagonist/killer and reduced Bcl2 expression. The decreased Bcl2 expression has been hypothesised to be a crucial factor for the inability of uremic lymphocytes for relieving apoptosis . Our findings support the concept that apoptosis route (by decrease Bcl2) is a pathogenic process of kidney injury induced by diabetic inflammation mechanisms. Additionally, understanding the role of IL-1β, IL-17, IL-33, and Bcl2 in diabetic patients can help in the early identification of individuals at risk of DN. Therefore, IL-1β, IL-17, IL-33, and Bcl2 are novel effective therapeutic goals for diabetic complications management.
The limitations of this study may be related to the sample size of each group, data on medications in detail, physical activity, and smoking screening. In addition, the limitations of examined some investigations such as eGFR, a number of the novel cytokines-associated with renal diseases.