Mineralocorticoid interaction with glycated albumin downregulates NRF – 2 signaling pathway in renal cells: Insights into diabetic nephropathy

Gaikwad, Deepesh D.; Bangar, Nilima; Apte, Mayura M.; Mistry, Armaan G.; Tupe, Rashmi S.

doi:10.1016/j.ijbiomac.2022.08.095

Cited by 13 publications

(16 citation statements)

References 84 publications

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“…Aldo can have this interaction as a RAGE-dependent or independent mechanism. Our earlier study reported static and spontaneous interaction between Aldo and glycated HSA . Thus, this study emphasizes evaluating the Aldo effect on glycation modifications of albumin and RAGE expression in HEK-293T cells.…”

Section: Introductionmentioning

confidence: 77%

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Crosstalk between Aldosterone and Glycation through Rac-1 Induces Diabetic Nephropathy

Apte,

Khan,

Bangar

et al. 2023

ACS Omega

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Background: Advanced glycation end products (AGEs) interaction with its receptor (RAGE) and aldosterone (Aldo) through the mineralocorticoid receptor (MR) activates Rac-1 and NF-κB independently in diabetic nephropathy (DN). However, the crosstalk of Aldo with AGEs-RAGE is still unresolved. Our study examined the impact of the AGEs-Aldo complex on renal cells and its effect on the RAGE-MR interaction. Methods and results: Glycation of human serum albumin (HSA) (40 mg/mL) with methylglyoxal (10 mM) in the presence of Aldo (100 nM) and aminoguanidine (AG) (100 nM) was performed. Glycation markers such as fructosamine and carbonyl groups and fluorescence of AGEs, pentosidine, and tryptophan followed by protein modification were measured. Renal (HEK-293T) cells were treated with the glycated HSA-Aldo (200 μg/mL) along with FPS-ZM1 and spironolactone antagonists for RAGE and Aldo, respectively, for 24 h. Glycation markers and esRAGE levels were measured. Protein and mRNA levels of RAGE, MR, Rac-1, and NF-κB were estimated. Glycation markers were enhanced with Aldo when albumin was only 14–16% glycated. AGEs-Aldo complex upregulated RAGE, MR, Rac-1 and NF-κB expressions. However, FPS-ZM1 action might have activated the RAGE-independent pathway, further elevating MR, Rac-1, and NF-κB levels. Conclusion: Our study concluded that the presence of Aldo has a significant impact on glycation. In the presence of AGEs-Aldo, RAGE-MR crosstalk exerts inflammatory responses through Rac-1 in DN. Insights into this molecular interplay are crucial for developing novel therapeutic strategies to alleviate DN in the future.

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Section: Introductionmentioning

confidence: 77%

“…30 Our recent study showed that Aldo binds to HSA with high affinity which is static and spontaneous. 15 Pharmacology relevant range of aminoguanidine concentration is reported to be 10−50 μM. 31 In the present study, 100 nM concentration of Aldo is used.…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between Aldosterone and Glycation through Rac-1 Induces Diabetic Nephropathy

Apte,

Khan,

Bangar

et al. 2023

ACS Omega

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“…GA is a non-enzymatic glycosylation product of plasma albumin and glucose, which reflects the glycemic control of the diabetic patients in the last 2 to 3 weeks [22]. Several recent studies have revealed that upregulated GA is significantly related to the presence of DN [23,24].…”

Section: Discussionmentioning

confidence: 99%

Upregulated Serum Glycated Albumin Contributes To Early Diabetic Nephropathy Diagnosis

2023

J Diabetes Treat

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Background Glycated albumin (GA) has been recently used as a glycemic marker for monitoring glucose control in type 2 diabetic mellitus (T2DM) patients, but its role in early diabetic nephropathy (EDN) in T2DM remains unclear. This study aims to investigate the clinical significance of GA in diagnosing EDN in T2DM patients. Methods and Results118 T2DM patients were enrolled and classified by the urine albumin/creatinine ratio (UACR) into groups of T2DM (UACR < 30 mg/g), EDN (early diabetic nephropathy 30 mg/g < UACR < 300mg/g) and ADN (advanced diabetic nephropathy, UACR > 300mg/g), and 36 healthy subjects were established as the control. Serum GA measured and the relevant clinical data were collected and analyzed. Our results disclosed significantly upregulated GA levels in EDN patients. Correlation analysis showed that in diabetes, GA was positively correlated with age(r=0.349, P=0.000), Ur(r=0.189, P=0.020), BMI(r=0.321, P=0.000), TBA(r=0.170, P=0.035), TG(r=0.227, P=0.005) and HbA1c(r=0.632, P=0.000), while negatively correlated with ALB(r=-0.227, P=0.001), mic-Alb(r=-0.271, P=0.004) and UAER(r=-0.475, P=0.003). Multiple linear regression found that GA was influenced by HbA1c and BMI. Univariate logistic regression demonstrated that upregulated GA, mic-Alb, ALB and Scr may be related to the progression of T2DM into EDN. Maybe due to insufficient sample size, mic-Alb rather than GA was included in the multivariate regression variance as a risk factor for the progression of T2DM to EDN. ROC analysis manifested that GA was a prominent indicator of EDN (AUC = 0.780, 95% CI 0.686-0.874, P<0.01) at cutoff values 16.705 % (sensitivity 0.900, specificity 0.525) in total T2DM patients. Noticeably, GA presented a better application value in the female where the AUC came up to 0.882 (95% CI: 0.768-0.997, P<0.01) with both high sensitivity (0.889) and high specificity (0.853) at the cutoff value of 23.365%. ConclusionUpregulation of GA appears positively related to the presence of EDN and contributes to its diagnosis.

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“…Kang et al (32) demonstrated that AGE significantly increases VEGF mRNA expression in cells, indicating a positive correlation between AGE and VEGF levels. Moreover, recent research on diabetic nephropathy revealed that blocking receptors for AGE reduces aldosterone's negative impact on NRF2 signal mediators in renal cells, suggesting that aldosterone may block the binding of AGE and RAGE to reduce VEGF production and affect NRF2, leading to corresponding harm to the retina (33). Therefore, aldosterone may play a role in regulating angiogenesis through its effect on VEGF, thus playing a therapeutic role in DR.…”

Section: Effect Of Aldosterone-mediated Angiogenesis On Diabetic Reti...mentioning

confidence: 99%

The role of aldosterone in the pathogenesis of diabetic retinopathy

et al. 2023

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Aldosterone, as a mineralocorticoid of adrenal origin, has effects that are not limited to the urinary tract. As an important regulator in Vasoactive hormone pathways, aldosterone may play an effect in the pathogenesis of diabetic retinopathy (DR) through the regulation of oxidative stress, vascular regulation, and inflammatory mechanisms. This implies that mineralocorticoids, including aldosterone, have great potential and value for the diagnosis and treatment of DR. Because early studies did not focus on the intrinsic association between mineralocorticoids and DR, targeted research is still in its infancy and there are still many obstacles to its application in the clinical setting. Recent studies have improved the understanding of the effects of aldosterone on DR, and we review them with the aim of exploring possible mechanisms for the treatment and prevention of DR.

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Mineralocorticoid interaction with glycated albumin downregulates NRF – 2 signaling pathway in renal cells: Insights into diabetic nephropathy

Cited by 13 publications

References 84 publications

Crosstalk between Aldosterone and Glycation through Rac-1 Induces Diabetic Nephropathy

Crosstalk between Aldosterone and Glycation through Rac-1 Induces Diabetic Nephropathy

Upregulated Serum Glycated Albumin Contributes To Early Diabetic Nephropathy Diagnosis

The role of aldosterone in the pathogenesis of diabetic retinopathy

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