Diabetic Nephropathy from RAAS to Autophagy: The Era for New Players

Nakhoul, Rola; Nakhoul, Farid; Nakhoul, Nakhoul

doi:10.21767/2472-5056.100043

Cited by 7 publications

(10 citation statements)

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“…Immunohistochemical results showed that cell loss in renal cortex of DN group is associated with significant decrease in H score of LC3 when compared with control group, which was consistent with previous results [46]. Impaired autophagy may be involved in the pathogenesis of podocyte loss, leading to massive proteinuria with progression of DN to end-stage renal failure [48]. Hyperglycemia inhibits Jun N-terminal kinase (JNK) signaling and enhances the interaction between Beclin-1 and Beclin-2 resulting in autophagy inhibition [49].…”

Section: Discussionsupporting

confidence: 90%

Autophagy and mTOR Pathways Mediate the Potential Renoprotective Effects of Vitamin D on Diabetic Nephropathy

Khodir

Samaka

Ameen

2020

International Journal of Nephrology

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Introduction. Not only is diabetic nephropathy (DN) the most common cause of end-stage renal disease worldwide, but it also increases the risk of mortality up to fourteen times compared to normoalbuminuric diabetic patients. Aim. The aim of the current study was the evaluation of the renoprotective effects of vitamin D in DN and the possible interplay between autophagy and mTOR pathways. Materials and Methods. Fifty male Wistar albino rats were divided (10/group) into control, DN group, insulin-treated DN group, vitamin D-treated DN group, and combined insulin and vitamin D-treated DN group. Assessments of systolic blood pressure, albuminuria, creatinine clearance, serum glucose, insulin, urea, creatinine, inflammatory cytokines, oxidative stress markers, and rat kidney gene expression of mTOR were performed. Histopathological and immunohistochemical assessments of autophagy marker LC3 in rat kidneys were also performed. Results. DN was associated with significant increases in SBP, urinary albumin, serum glucose, urea, creatinine, inflammatory cytokines, MDA, and mTOR gene expression (P<0.05). However, there was significant decrease in creatinine clearance, serum insulin, GSH, and H score value of LC3 when compared with control group (P<0.05). The combination of insulin and vitamin D treatment significantly restored DN changes when compared with the other treated groups, except in oxidative stress markers where there was an insignificant difference between the combination-treated and insulin-treated groups (P>0.05). Conclusion. It has been concluded that vitamin D is a potent adjuvant therapy in treatment of DN via downregulation of mTOR gene expression, stimulation of autophagy, and antioxidant, anti-inflammatory, and hypotensive effects.

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Section: Discussionsupporting

confidence: 90%

Autophagy and mTOR Pathways Mediate the Potential Renoprotective Effects of Vitamin D on Diabetic Nephropathy

Khodir

Samaka

Ameen

2020

International Journal of Nephrology

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“…The main pathological changes in DN include functional changes manifested by hyperfiltration and morphological changes in the glomerulus and proximal convoluted tubule (PCT) cells, with podocyte effusion, mesangial matrix hyperplasia, extracellular matrix (ECM) expansion, tubulointerstitial fibrosis, and glomerular sclerosis, leading to ESRD [ 5 – 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…These lead to the release of reactive oxygen species and oxidative stress and inflammatory mediators. Several studies have demonstrated that inflammatory cytokines and proinflammatory factors are closely associated with DN generation and progression [ 6 , 7 ]. Moreover, it is known that renal fibrosis is caused by renal hemodynamic changes, ischemia, glucose metabolism abnormalities, and an overactive renin-angiotensin-aldosterone system (RAAS) [ 5 , 8 , 9 – 11 ].…”

Section: Introductionmentioning

confidence: 99%

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The Therapeutic Effect of Active Vitamin D Supplementation in Preventing the Progression of Diabetic Nephropathy in a Diabetic Mouse Model

Nakhoul

Thawko

Farber

et al. 2020

Journal of Diabetes Research

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Background. Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes and is the leading cause of end-stage renal disease (ESRD) and replacement therapy worldwide. Vitamin D levels in DN patients are very low due to the decrease in the synthesis and activity of 1-α hydroxylase in the proximal tubule cells and decrease in the vitamin D receptor abundance. To date, few studies have shown the antioxidant effects of 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] on hyperglycemia-induced renal injury. The selective activator of the vitamin D receptor, paricalcitol, reduces proteinuria and slows the progression of kidney injury. The precise mechanism through which vitamin D affects diabetic status and provides kidney protection remains to be determined. Methods. Diabetes mellitus (DM) was induced in 94 8-week-old DBA/2J mice by intraperitoneal injection of streptozotocin (STZ). DM mice were randomly divided into receiving vehicle or treatment with paricalcitol, the active vitamin D analog, 1 week after DM induction or paricalcitol treatment 3 weeks after DM induction. An additional control group of healthy wild-type mice was not treated. Urine albumin, blood urea nitrogen, and creatinine levels were measured before and at the end of the paricalcitol treatment. Periodic acid-Schiff, immunohistochemistry staining, and western blot of the renal tissues of vitamin D receptor, villin, nephrin, and podocin expressions, were analyzed. Results. Paricalcitol treatment restored villin, nephrin, and podocin protein levels that were downregulated upon DM induction, and reduced fibronectin protein level. Vitamin D receptor activation by paricalcitol may reduce proteinuria of DN in mice and alleviate high-glucose-induced injury of kidney podocytes by regulating the key molecules such nephrin-podocin. Conclusions. Paricalcitol treatment was associated with improved structural changes in type 1 diabetic mice including upregulation of vitamin D receptor expression, and decreased fibrosis markers such as fibronectin. These effects may contribute to the consistent benefit of vitamin D analog to slow the deterioration in glomerular function and reduce the risk of ESRD in patients with type 1 and 2 diabetes mellitus. Our results suggest that additional use of paricalcitol may be beneficial in treating patients with diabetes under standard therapeutic strategies.

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“…With consequences of reactive oxygen species(ROS) generation, inflammation, over expression of transforming growth factor-β (TGF-β), and deregulations of different vascular growth factors such as the vascular endothelial growth factor-A (VEGF-A) (8) . Activating local (RAAS) results in increased angiotensin II (Ang II), in addition to action Adrenoctincorticotrpic hormone ( ACTH ), and potassium are three principal factors that adjusted aldosterone secretion (9,10) .…”

Section: Introductionmentioning

confidence: 99%

Serum Aldosterone Levels in Patients With Diabetic Nephropathy in Relation to Vascular Calcification

Salih¹,

Ali²,

Al-Lehibi³

2019

IJPS

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Diabetic Nephropathy(DN) is a complex disease manifested by persistence microalbuminuria occurring due to the interaction between hemodynamic and metabolic pathway that activates the local renin-angiotensin-aldosterone system resulting in a decline in renal functions. This study aimed to quantify the associations between serum aldosterone concentration and fetuin- A as a marker of calcification in type 2 diabetic patients with and without microalbuminuria from one side, and study the possible relationship between aldosterone and fetuin-A with glycemic indices, serum electrolyte, renal function and microalbuminuria and body mass index from the other side. A case-control study involved eighty-six adult subjects classified into three groups after testing urine microalbumin including thirty-two diabetics type 2 patients with positive microalbuminuria and twenty-eight diabetics type 2 patients with negative microalbuminuria and 26 healthy subjects during their visit to AL kindy specialized Center for Endocrinology and Diabetes / Baghdad. Those patients were compared to control group of 26 apparently healthy subjects, fasting blood samples was obtained from each of them in one occasion only to measure: fasting serum glucose, electrolyte, aldosterone, fetuin-A, urea, and creatinine. In addition to glycoheamoglobin, glomerular filtration rate and body mass index. Despite the presence of microalbuminuria in thirty-two of the studied diabetics, there was no positive correlation between aldosterone and fetuin- A, besides that no significant variations in serum aldosterone ,glomerular filtration rate(GFR) values, while both groups showed a significant increase in fasting serum glucose and glycaoheamoglobin ,significant decrease in serum sodium and chloride in comparison with the control group , significant increase was detected in serum fetuin-A mean values in microalbuminuric diabetics. Whereas, negative microalbuminuric diabetics measures expressed a positive correlation between both serum sodium and chloride levels and fetuin -A. The conclusion of this study diabetic patient are prone to vascular calcification (VC) might be due to increase in aldosterone level or due to diabetic itself from this study we can conclude microalbuminuria can occur without a decline in renal function or a change in estimated GFR ,no definite correlation occur between aldosterone and fetuin- A, fetuin- A mean values are higher in diabetic patient with microalbuminuria compared to diabetic patients without microalbuminuria and control group and this referred to uncontrolled diabetes ,aldosterone show a correlation with weight and body mass index while fetuin- A does not show such correlation. In general, electrolyte disturbances (hypernatremia) is more obvious in this study , and its occurrence is due to diabetic (osmotic diuresis) or drugs, while sodium retention which is a sign of aldosterone increment does not occur. Hypochloremia that occur in this study is due to chloride and it is in parallel with sodium level.

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Diabetic Nephropathy from RAAS to Autophagy: The Era for New Players

Cited by 7 publications

References 58 publications

Autophagy and mTOR Pathways Mediate the Potential Renoprotective Effects of Vitamin D on Diabetic Nephropathy

Autophagy and mTOR Pathways Mediate the Potential Renoprotective Effects of Vitamin D on Diabetic Nephropathy

The Therapeutic Effect of Active Vitamin D Supplementation in Preventing the Progression of Diabetic Nephropathy in a Diabetic Mouse Model

Serum Aldosterone Levels in Patients With Diabetic Nephropathy in Relation to Vascular Calcification

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