Protective effects of aliskiren and valsartan in mice with diabetic nephropathy

Wang, Weidong; Qiu, Liru; Howard, Allison; Solis, Nathaniel; Li, Chunling; Wang, Xiaoxin; Kopp, Jeffrey B.; Levi, Moshe

doi:10.1177/1470320313507123

Cited by 33 publications

(31 citation statements)

References 53 publications

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“…In contrast in rodent diabetic kidney disease low dose irbesartan reduces albuminuria and inflammation, but does not reduce ER stress (calnexin and GRP78/BiP staining) [200]. Valsartan (an ARB) and aliskiren (direct renin inhibitor) also reduce CHOP and XBP-1 expression in rodent diabetic kidneys [201]. Thus the beneficial effects of renin-angiotensin system blockade, may be in part related to modulation of ER stress.…”

Section: Modulation Of Er Stressmentioning

confidence: 99%

Endoplasmic Reticulum Stress in the Diabetic Kidney, the Good, the Bad and the Ugly

Cunard

2015

JCM

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Diabetic kidney disease is the leading worldwide cause of end stage kidney disease and a growing public health challenge. The diabetic kidney is exposed to many environmental stressors and each cell type has developed intricate signaling systems designed to restore optimal cellular function. The unfolded protein response (UPR) is a homeostatic pathway that regulates endoplasmic reticulum (ER) membrane structure and secretory function. Studies suggest that the UPR is activated in the diabetic kidney to restore normal ER function and viability. However, when the cell is continuously stressed in an environment that lies outside of its normal physiological range, then the UPR is known as the ER stress response. The UPR reduces protein synthesis, augments the ER folding capacity and downregulates mRNA expression of genes by multiple pathways. Aberrant activation of ER stress can also induce inflammation and cellular apoptosis, and modify signaling of protective processes such as autophagy and mTORC activation. The following review will discuss our current understanding of ER stress in the diabetic kidney and explore novel means of modulating ER stress and its interacting signaling cascades with the overall goal of identifying therapeutic strategies that will improve outcomes in diabetic nephropathy.

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Section: Modulation Of Er Stressmentioning

confidence: 99%

Endoplasmic Reticulum Stress in the Diabetic Kidney, the Good, the Bad and the Ugly

Cunard

2015

JCM

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“…Aliskiren, the only available orally effective DRI, has been demonstrated to be effective in blood pressure reduction and end-organ protection, such as cardiovascular and renal protection in preclinical and clinical experiments. In addition, aliskiren has been shown to protect kidneys from acute kidney injuries induced by either contrast (23) or ischemia-reperfusion (17,50) or by chronic kidney diseases (e.g., in diabetic nephropathy) (22,49) as well as by doxorubicin-induced nephrotoxicity (39). Aliskiren alone or in combination with other drugs has also been shown to attenuate renal fibrosis and inflammation induced by ureteral obstruction (8,42,52).…”

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confidence: 99%

“…Several studies have also demonstrated that blockade of the RAS attenuates the expression of an array of cytokines and growth factors with important roles in the impairment of renal functions in rats with unilateral ureteral obstruction (UUO) (8,18,52). Currently, drugs targeting the RAS, including direct renin inhibitors (DRIs), ACE inhibitors, ARBs, and aldosterone blockers have been most widely used for slowing or preventing renal damage in chronic kidney diseases (49).…”

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confidence: 99%

Aliskiren restores renal AQP2 expression during unilateral ureteral obstruction by inhibiting the inflammasome

Wang

Luo

Lin

et al. 2015

American Journal of Physiology-Renal Physiology

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Ureteral obstruction is associated with reduced expression of renal aquaporins (AQPs), urinary concentrating defects, and an enhanced inflammatory response, in which the renin-angiotensin system (RAS) may play an important role. We evaluated whether RAS blockade by a direct renin inhibitor, aliskiren, would prevent the decreased renal protein expression of AQPs in a unilateral ureteral obstruction (UUO) model and what potential mechanisms may be involved. UUO was performed for 3 days (3UUO) and 7 days (7UUO) in C57BL/6 mice with or without aliskiren injection. In 3UUO and 7UUO mice, aliskiren abolished the reduction of AQP2 protein expression but not AQP1, AQP3, and AQP4. mRNA levels of renal AQP2 and vasopressin type 2 receptor were decreased in obstructed kidneys of 7UUO mice, which were prevented by aliskiren treatment. Aliskiren treatment was also associated with a reduced inflammatory response in obstructed kidneys of UUO mice. Aliskiren significantly decreased mRNA levels of several proinflammatory factors, such as transforming growth factor-β and tumor necrosis factor-α, seen in obstructed kidneys of UUO mice. Interestingly, mRNA and protein levels of the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome components apoptosis-associated speck-like protein containing a caspase recruitment domain, caspase-1, and IL-1β were dramatically increased in obstructed kidneys of 7UUO mice, which were significantly suppressed by aliskiren. In primary cultured inner medullary collecting duct cells, IL-1β significantly decreased AQP2 expression. In conclusions, RAS blockade with the direct renin inhibitor aliskiren increased water channel AQP2 expression in obstructed kidneys of UUO mice, at least partially by preventing NLRP3 inflammasome activation in association with ureteral obstruction.

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“…Studies shows that the renin inhibitor (aliskiren) ameliorates renal damage in diabetic TG (mREN-2) rats (Kelly et al, 2007; Feldman et al, 2008) or in type 1 or 2 diabetics (Parving et al, 2008; Wang et al, 2014). ACE inhibitors (ACEI) or AT1 receptor antagonists reduce mesangial sclerosis and proteinuria in animal models of both type 1 and type 2 diabetes (Andersen et al, 2000; Chan et al, 2000; Lewis et al, 2001; Brenner et al, 2001; Lewis, 2002; Carey and Siragy, 2003).…”

Section: The Renin Angiotensin System (Ras) and Dnmentioning

confidence: 99%

Role of upstream stimulatory factor 2 in diabetic nephropathy

Wang

2015

Front. Biol.

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Diabetic nephropathy (DN) is the most common cause of end-stage renal disease (ESRD). About 20%–30% of people with type 1 and type 2 diabetes develop DN. DN is characterized by both glomerulosclerosis with thickening of the glomerular basement membrane and mesangial matrix expansion, and tubulointerstitial fibrosis. Hyperglycemia and the activation of the intra-renal renin-angiotensin system (RAS) in diabetes have been suggested to play a critical role in the pathogenesis of DN. However, the mechanisms are not well known. Studies from our laboratory demonstrated that the transcription factor—upstream stimulatory factor 2 (USF2) is an important regulator of DN. Moreover, the renin gene is a downstream target of USF2. Importantly, USF2 transgenic (Tg) mice demonstrate a specific increase in renal renin expression and angiotensin II (AngII) levels in kidney and exhibit increased urinary albumin excretion and extracellular matrix deposition in glomeruli, supporting a role for USF2 in the development of diabetic nephropathy. In this review, we summarize our findings of the mechanisms by which diabetes regulates USF2 in kidney cells and its role in regulation of renal renin-angiotensin system and the development of diabetic nephropathy.

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Protective effects of aliskiren and valsartan in mice with diabetic nephropathy

Cited by 33 publications

References 53 publications

Endoplasmic Reticulum Stress in the Diabetic Kidney, the Good, the Bad and the Ugly

Endoplasmic Reticulum Stress in the Diabetic Kidney, the Good, the Bad and the Ugly

Aliskiren restores renal AQP2 expression during unilateral ureteral obstruction by inhibiting the inflammasome

Role of upstream stimulatory factor 2 in diabetic nephropathy

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