Therapies on the Horizon for Diabetic Kidney Disease

Khan, Sadaf; Quaggin, Susan E.

doi:10.1007/s11892-015-0685-3

Cited by 33 publications

(30 citation statements)

References 61 publications

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“…Diabetic Kidney Disease (DKD) is the main cause of end-stage renal disease [1][2]. It has been established that hyperglycemia plays a crucial role in the pathogenesis of DKD.…”

Section: Introductionmentioning

confidence: 99%

Activation of the Nrf2-ARE Pathway Ameliorates Hyperglycemia-Mediated Mitochondrial Dysfunction in Podocytes Partly Through Sirt1

Zhang¹,

Deng²,

Zhang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Previously we have shown that activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-antioxidant response element (ARE) attenuated hyperglycemia-induced damage in podocytes, but the molecular mechanism remains unknown. Methods: Tert-butylhydroquinone (t-BHQ) and small interfering RNAs (siRNAs) were used to regulate Nrf2 expression, while nicotinamide and siRNAs were used to regulate sirtuin 1 (Sirt1) activity and expression, respectively. Mitochondrial superoxide, membrane potential and ATP levels were measured to assess changes in mitochondrial function. Nephrin and synaptopodin expression were measured by western blot analysis. Human podocytes and db/db diabetic mice were used in this study. Results: t-BHQ pretreatment of human podocytes exposed to high glucose (HG) alleviated mitochondrial dysfunction, enhanced the expression of Sirt1, nephrin and synaptopodin and lowered BSA permeability compared with podocytes exposed to HG without t-BHQ pretreatment (p< 0.05). Human podocytes exposed to HG had more severe mitochondrial dysfunction, lower expression of Sirt1, synaptopodin and nephrin and higher BSA permeability than podocytes exposed to HG when Nrf2 expression was downregulated by siRNAs (p< 0.05). The protection provided by activation of the Nrf-ARE pathway in podocytes exposed to HG was partially diminished when Sirt1 expression or activity was decreased by siRNAs or inhibitor compared with podocytes exposed to HG and pretreated with t-BHQ (p< 0.05). When nicotinamide and t-BHQ were both administered to db/db mice, we observed higher levels of urinary albumin/creatinine, lower nephrin and synaptopodin expression, more severe mesangial matrix deposition, collagen deposition on pathological slides and mitochondrial structural damage in podocytes compared to db/db mice treated only with t-BHQ. Conclusions: Our findings suggest that crosstalk between Sirt1 and the Nrf2-ARE anti-oxidative pathway forms a positive feedback loop and that protection provided by t-BHQ activation of the Nrf2-ARE pathway in db/db mice is partly dependent on Sirt1.

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“…Diabetic Kidney Disease (DKD) is the main cause of end-stage renal disease [1][2]. It has been established that hyperglycemia plays a crucial role in the pathogenesis of DKD.…”

Section: Introductionmentioning

confidence: 99%

Activation of the Nrf2-ARE Pathway Ameliorates Hyperglycemia-Mediated Mitochondrial Dysfunction in Podocytes Partly Through Sirt1

Zhang¹,

Deng²,

Zhang³

et al. 2018

Cell Physiol Biochem

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show abstract

“…More than 90% of diabetic patients have type 2 diabetes and at least 70% are hypertensive 1–4 . Hypertension in obese patients with type 2 diabetes is often difficult to control 5, 6 . Surveys of responding diabetic patients indicate that 85% were taking antihypertensive drugs but only 36% had blood pressure (BP) controlled to the goal of <130/80 mmHg 7, 8 .…”

Section: Introductionmentioning

confidence: 99%

Synergistic Interaction of Hypertension and Diabetes in Promoting Kidney Injury and the Role of Endoplasmic Reticulum Stress

et al. 2017

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Diabetes mellitus and hypertension are major risk factors for chronic kidney injury, together accounting for >70% of end-stage renal disease. In this study, we assessed interactions of hypertension and diabetes in causing kidney dysfunction and injury and the role of endoplasmic reticulum (ER) stress. Hypertension was induced by aorta constriction (AC) between the renal arteries in 6-month old male Goto-Kakizaki (GK) type 2 diabetic and control Wistar rats. Fasting plasma glucose averaged 162±11 and 87±2 mg/dL in GK and Wistar rats, respectively. AC produced hypertension in the right kidney (above AC) and near normal blood pressure (BP) in the left kidney (below AC), with both kidneys exposed to the same levels of glucose, circulating hormones, and neural influences. After 8 wks of AC, BP above the AC (and in the right kidney) increased from 109±1 to 152±5 mmHg in GK rats and from 106±4 to 141±5 mmHg in Wistar rats. The diabetic-hypertensive right kidneys in GK-AC rats had much greater increases in albumin excretion and histological injury compared to left kidneys (diabetes only) of GK rats or right kidneys (hypertension only) of Wistar-AC rats. Marked increases in ER stress and oxidative stress indicators were observed in diabetic-hypertensive kidneys of GK-AC rats. Inhibition of ER stress with tauroursodeoxycholic acid (TUDCA) for 6 wks reduced BP (135±4 vs 151±4 mmHg), albumin excretion, ER and oxidative stress, glomerular injury, while increasing GFR in hypertensive-diabetic kidneys. These results suggest that diabetes and hypertension interact synergistically to promote kidney dysfunction and injury via ER stress.

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“…The metabolic abnormality and microvascular complications caused by the sustained hyperglycemia lead to diabetic nephropathy (DN) [1]. Diabetic kidney disease is the leading cause of morbidity and end-stage renal disease (ESRD) [2–4]. However, effective clinical interventions for DN have not yet been elucidated.…”

Section: Introductionmentioning

confidence: 99%

EGFR inhibition attenuates diabetic nephropathy through decreasing ROS and endoplasmic reticulum stress

Zhao

Zhong

et al. 2017

Oncotarget

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Diabetic nephropathy (DN) is a progressive kidney disease due to glomerular capillary damage in diabetic patients. Endoplasmic reticulum (ER) stress caused by reactive oxygen species (ROS) is associated with DN progression. Epidermal growth factor receptor (EGFR) mediates oxidative stress and damage of cardiomyocytes in diabetic mice. Here we demonstrated that AG1478, a specific inhibitor of EGFR, blocked EGFR and AKT phosphorylation in diabetic mice. Oxidative stress and ER stress markers were eliminated after AG1478 administration. AG1478 decreased pro-fibrotic genes TGF-β and collagen IV. Furthermore, we found that high glucose (HG) induced oxidative stress and ER stress, and subsequently increased ATF4 and CHOP. These changes were eliminated by either AG1478 or ROS scavenger N-acetyl-L-cysteine (NAC) administration. These results were confirmed by knock-down approaches in renal mesangial SV40 cells. However, AG1478, not NAC, reversed HG induced EGFR and AKT phosphorylation. These results suggest that EGFR/AKT/ROS/ER stress signaling plays an essential role in DN development and inhibiting EGFR may serve as a potential therapeutic strategy in diabetic kidney diseases.

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Therapies on the Horizon for Diabetic Kidney Disease

Cited by 33 publications

References 61 publications

Activation of the Nrf2-ARE Pathway Ameliorates Hyperglycemia-Mediated Mitochondrial Dysfunction in Podocytes Partly Through Sirt1

Activation of the Nrf2-ARE Pathway Ameliorates Hyperglycemia-Mediated Mitochondrial Dysfunction in Podocytes Partly Through Sirt1

Synergistic Interaction of Hypertension and Diabetes in Promoting Kidney Injury and the Role of Endoplasmic Reticulum Stress

EGFR inhibition attenuates diabetic nephropathy through decreasing ROS and endoplasmic reticulum stress

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