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Diabetic nephropathy is a leading cause of end-stage renal disease (ESRD) and increased cardiovascular morbidity and mortality worldwide in patients with type 2 diabetes mellitus. The mechanisms behind the pathophysiology of DN are complex and continue to be not fully understood. Both metabolic (hyperglycaemia) and haemodynamic alterations interact synergistically, and have been reported to activate local RAAS resulting in increased angiotensin-2. In spite the early and chronic treatment with converting enzyme inhibitors and angiotensin receptor blocking drugs, the number of patients reaching end stage renal disease and replacement therapy are increasing.Recently different pathways were proposed to be involved in the pathogenesis of diabetic nephropathy, including the autophagy process, Klotho and the selective agonist vitamin D and his receptor. Under hyperglycemic stress especially in podocytes and proximal convolute tubule cells, there is decrease in the protective autophagic process and increase in cellular damage.α-Klotho is a multifunctional protein highly expressed in the kidney. The klotho protein has endogenous anti fibrotic function via antagonism of Wnt/β-catenin signaling, which promotes fibrogenesis, suggesting that loss of Klotho in early stage of diabetic nephropathy may contribute to the progression of DN by accelerated fibrogenesis.The selective vitamin D agonist and his receptor, play a protective pathway in diabetic nephropathy. A key renoprotective function of vitamin D is to reduce albuminuria or proteinuria, major risk factors for CKD progression, renal failure, cardiovascular events, and death. This antiproteinuric effect and the deceleration of DN progression is mediated primarily via the blocking of the renin angiotensin aldosterone system. In this review we will discuss the different new mechanisms involved in diabetic nephropathy and future therapeutic agents like the mTorc1 blocker, Rapamycin, that can upregulate the autophagy process, the new sodium-glucose transport inhibitors and Paricalcitol, the selective active vitamin D.

SARS-CoV-2, causing the lethal disease COVid-19, is a public health emergency in the 2020 global pandemic. The outbreak and fast spreading of SARS-CoV-2 have a high morbidity and mortality specifically in elder patients with chronic diseases such as diabetes mellitus, arterial hypertension, chronic kidney disease, and organ transplanted patients with immunosuppressive therapy. Preliminary results support different treatments such as chloroquine and convalescent plasma infusion in severe cases, with good outcome. On the other hand, the efficacy of supplementation with active vitamin D, an immunomodulator hormone with antiinflammatory and antimicrobial effects, is unproven. A recent study reported that vitamin D attains antiviral effects, via blocking viral replication directly. SARS-CoV-2 primarily uses the immune evasion process during infection via the envelope spike glycoprotein, which is followed by a cytokine storm, causing severe acute respiratory disease syndrome and death. SARS-CoV-2, by using the well-known angiotensin-converting enzyme 2 by the protein spike, as the host receptor to enter into alveolar, myocardial, and renal epithelial cells, can be disrupted by vitamin D. However, the correlation between vitamin D levels and COVID-19 deaths in previous studies was insignificant. Retrospective studies demonstrated a correlation between vitamin D status and COVID-19 severity and mortality, while other studies did not find this correlation. Studies have shown that, vitamin D reduces the risk of acute viral respiratory tract infections and pneumonia via direct inhibition of viral replication, antiinflammatory and immunomodulatory effects. The data available today regarding the beneficial protective effect of vitamin D is unclear and with conflicting results. Large randomized control trials are necessary to test this hypothesis. In this review, we will explain the cross talk between the active vitamin D and the angiotensin-converting enzyme 2, and summarize the data from the literature. Keywords Angiotensin converting enzyme 2 . COVID-19 . Renin . SARS-CoV-2 . Vitamin D Abbreviation ACE2 Angiotensin converting enzyme 2 VDR Vitamin D receptor RAAS Renin angiotensin-aldosterone system AII Angiotensin II AI Angiotensin I

Background Autophagy is a catabolic mechanism that involves lysosomal-dependent degradation of unnecessary intracellular components and responsible for normal cellular homeostasis. Autophagy pathway and its key participant ATG5/LC3 are associated with several pathologies such as diabetes mellitus and its complications. Methods Levels and expression of autophagy key components ATG5 and LC3B were analyzed in both human model and murine tissues. One hundred and twenty human subjects were divided into four groups: Healthy (control), diabetes mellitus without complications, diabetic nephropathy, and diabetic retinopathy. Additionally, we used kidneys from WT healthy and diabetic nephropathy mice. Lysate derived from human peripheral blood mononuclear cells and murine renal cortex lysates were subjected to western blot and immunohistochemical analysis. Results Western blot and immunohistochemical analysis demonstrate that ATG5 protein levels were significantly decreased in diabetes mellitus, diabetic nephropathy (DN), and diabetic retinopathy patients versus healthy controls and in DN mice compared to healthy mice (0.65 ± 0.04; 1.15 ± 0.13 A.U. units, respectively). Quantification of staining area (%) of ATG5 mice tissue expression also decreased in DN versus healthy mice (4.42 ± 1.08%; 10.87 ± 1.01%, respectively). LC3B levels and expression Significant reduction in peripheral blood mononuclear cells in diabetic patients (with or without complications) vs. healthy controls. Renal LC3B levels were lower in DN versus healthy mice (0.36 ± 0.03; 0.68 ± 0.07 A.U. units). Renal LC3B staining quantification revealed significant reduction in DN versus healthy mice (1.7 ± 0.23%; 8.56 ± 1.7%). Conclusion We conclude that ATG5, as well as LC3B, are down regulated in diabetic patients with or without complications. This diminution contributes to deficiencies in the autophagy process.

Background. Type 2 diabetes mellitus (T2DM), especially hyperglycemia, is associated with increased glucose cell toxicity and oxidative stress that can lead to irreversible damage in the kidney such as diabetic nephropathy (DN). Autophagy plays a key role in the degradation of damaged intracellular proteins in order to maintain intracellular homeostasis and cell integrity. The disturbance of autophagy is involved in the pathogenesis of diabetic nephropathy. We aim to investigate the molecular effect of sodium-glucose transporter 2 inhibitor (SGLT2i) on the expression of ATG5 and its downstream collaborator LC3-II in diabetic nice model. Material and Methods. We used eight weeks old male mice: twenty C57BL/6 wild type (C57BL/6), twenty BTBR ob/ob (DM), and twenty BTBR ob/ob that were treated with empagliflozin (DM+EMPA), FDA approved SGLT2i. Lysate from murine renal cortex was analyzed by Western blot and immunohistochemistry. ATG5, LC3B, and fibronectin expression were analyzed in murine kidney tissues. All mice were sacrificed 13 weeks after the beginning of the experiment. Results. Histological and Western blot analyses reveal decrease ATG5, LC3-II, and fibronectin levels at renal specimens taken from DM mice. EMPA treatment reduced T2DM mice body weight and blood glucose and increased urine glucose. Further, it upregulated all of the abovementioned proteins. Conclusions. Hyperglycemia reduces LC3-II and ATG5 protein levels which contribute to deficiencies in the autophagy process, with development and progression of DN. SGLT2i significantly reduces progression of DN and onset of end-stage renal disease in T2DM patients, probably through its effect on autophagy.