Mechanistic insight of diabetic nephropathy and its pharmacotherapeutic targets: An update

Bhattacharjee, Niloy; Barma, Sujata; Konwar, Nandita; Dewanjee, Saikat; Manna, Prasenjit

doi:10.1016/j.ejphar.2016.08.022

Cited by 216 publications

(173 citation statements)

References 236 publications

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“…A large minority of patients with type 2 diabetes and reduced kidney function present with normal levels of albuminuria. These findings are consistent with a recent report in which the prevalence of albuminuria in patients with type 2 diabetes decreased from about 21% in 1988-1994 to 16% in 2009-2014, despite a rise in the prevalence of reduced estimated glomerular filtration rate (eGFR) [4,5].…”

Section: Introductionsupporting

confidence: 93%

“…Despite intensified pharmacologic interventions (e.g., antihyperglycemic agents, statins, and blood pressure lowering such as renin-angiotensin system [RAS] blockers) to strictly control these risk factors, the prevalence of diabetic nephropathy continues to rise and has become the leading cause for ESRD worldwide [58]. Moreover, DN is strongly associated with cardiovascular disease (CVD) and increased 10-year mortality from 12% in patients with T2D without DN to 31% in patients with DN.…”

Section: Sodium-glucose-co Transporter (Sgl2) Blockersmentioning

confidence: 99%

“…Specifically, it was associated with a statistically significant lower incidence rate of macroalbuminuria (38%), doubling of serum creatinine and eGFR# 45 ml/min per 1.73 m 2 (44%), and initiation of dialysis (55%). In addition, as we mentioned above, the sodium glucose transport type 2 inhibitor also can ameliorate the autophagy process that is down regulated in the proximal tubular cells due to hyperglycemia [57][58][59][60][61].…”

Section: Sodium-glucose-co Transporter (Sgl2) Blockersmentioning

confidence: 99%

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

Nakhoul¹,

Nakhoul²,

Nakhoul³

2017

J Clin Exp Nephrol

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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.

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Section: Introductionsupporting

confidence: 93%

Section: Sodium-glucose-co Transporter (Sgl2) Blockersmentioning

confidence: 99%

Section: Sodium-glucose-co Transporter (Sgl2) Blockersmentioning

confidence: 99%

See 1 more Smart Citation

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

Nakhoul¹,

Nakhoul²,

Nakhoul³

2017

J Clin Exp Nephrol

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“…Diabetic nephropathy is the primary cause of death in 21% of people with type 1 diabetes [4], and cardiovascular disease, which includes diabetic cardiomyopathy, accounts for 44% of all fatalities in type 1 diabetes [5]. Both pathologies are characterised by an impairment in function (kidney [proteinuria [6]], heart [impairment in systolic contractility [7]]) caused by local inflammation [8], endothelial dysfunction [9] and loss of survival pathways, the latter of which predisposes tissues to injury.…”

Section: Introductionmentioning

confidence: 99%

Annexin A1 attenuates microvascular complications through restoration of Akt signalling in a murine model of type 1 diabetes

et al. 2017

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Aims/hypothesis Microvascular complications in the heart and kidney are strongly associated with an overall rise in inflammation. Annexin A1 (ANXA1) is an endogenous anti-inflammatory molecule that limits and resolves inflammation. In this study, we have used a bedside to bench approach to investigate: (1) ANXA1 levels in individuals with type 1 diabetes; (2) the role of endogenous ANXA1 in nephropathy and cardiomyopathy in experimental type 1 diabetes; and (3) whether treatment with human recombinant ANXA1 attenuates nephropathy and cardiomyopathy in a murine model of type 1 diabetes. Methods ANXA1 was measured in plasma from individuals with type 1 diabetes with or without nephropathy and healthy donors. Experimental type 1 diabetes was induced in mice by injection of streptozotocin (STZ; 45 mg/kg i.v. per day for 5 consecutive days) in C57BL/6 or Anxa1 −/− mice. Diabetic mice were treated with human recombinant (hr)ANXA1(1 μg, 100 μl, 50 mmol/l HEPES; 140 mmol/l NaCl; pH 7.4, i.p.) or vehicle (100 μl, 50 mmol/l HEPES; 140 mmol/l NaCl; pH 7.4, i.p.).Results Plasma levels of ANXA1 were elevated in individuals with type 1 diabetes with/without nephropathy compared with healthy individuals (66.0 ± 4.2/64.0 ± 4 ng/ml vs 35.9 ± 2.3 ng/ml; p < 0.05). Compared with diabetic wild-type (WT) mice, diabetic Anxa1 −/− mice exhibited a worse diabetic phenotype and developed more severe cardiac (ejection fraction; 76.1 ± 1.6% vs 49.9 ± 0.9%) and renal dysfunction (proteinuria; 89.3 ± 5.0 μg/ mg vs 113.3 ± 5.5 μg/mg). Mechanistically, compared with nondiabetic WT mice, the degree of the phosphorylation of mitogenactivated protein kinases (MAPKs) p38, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) was significantly higher in non-diabetic Anxa1 −/− mice in both the heart and kidney, and was further enhanced after STZ-induced type 1 diabetes. Prophylactic treatment with hrANXA1 (weeks 1-13) attenuated both cardiac (ejection fraction; 54.0 ± 1.6% vs 72.4 ± 1.0%) and renal (proteinuria; 89.3 ± 5.0 μg/mg vs 53.1 ± 3.4 μg/mg) dysfunction associated with STZ-induced diabetes, while therapeutic administration of hrANXA1 (weeks 8-13), after significant cardiac and renal dysfunction had already developed, halted the further functional decline in cardiac and renal function seen in diabetic mice administered vehicle. In addition, administration of hrANXA1 attenuated the increase in phosphorylation of p38, JNK and ERK, and restored phosphorylation of Akt in diabetic mice. Conclusions/interpretationOverall, these results demonstrate that ANXA1 plasma levels are elevated in individuals with Christoph Thiemermann and Egle Solito contributed equally to this work.Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-017-4469-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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“…Using the UUO model, we then found that, during the fibrotic process, patchy promotion of tubular epithelial proliferation and survival, and interstitial cell apoptosis were linked spatially and temporally with increased pERK expression (12). There is evidence of an interactive mechanistic pathway between the MAPK signalling pathway and JAK/STAT signalling (18,19), and for a role for the JAK/ STAT pathway in kidney fibrosis (3)(4)(5)(6). In this study, where we investigated mRNA for JAK1, JAK2 and JAK3, only JAK3 mRNA had any marked change using the established in vitro model with cells central to development of fibrosis (tubular epithelium and renal fibroblasts).…”

Section: Discussionmentioning

confidence: 94%

Role of JAK3 in the Pathogenesis of Oxidative Stress-Induced Kidney Fibrosis

Pat

Johnson

Gobé

2018

jrenhep

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The Janus kinase (JAK) tyrosine kinase family and JAK/STAT signal transduction pathway may act in kidney fibrogenesis. JAK3 expression was investigated in in vitro and in vivo models of kidney fibrosis involving oxidative stress. There was a marked down-regulation of JAK3 mRNA in rat kidney tubular epithelial cells (NRK52E) and fibroblasts (NRK49F) exposed to 1.0 mM H 2 O 2 for 18-20 h compared with controls, which correlated with increased apoptosis and decreased mitosis in both cell lines. However, JAK3 protein levels were not significantly different in control and H2O2-treated epithelial and fibroblast cultures. JAK3 activation (phospho-tyrosine) increased in NRK52E cells and decreased in NRK49F cells with oxidative stress. STAT3 phosphorylation decreased in both cell lines with oxidative stress compared with controls. JAK3 protein expression and localisation were investigated in kidneys using the unilateral ureteral obstruction (UUO) model (0-7 days, rats) of kidney fibrosis that involves oxidative stress. JAK3 protein expression did not differ between UUO and controls; however, JAK3 localisation increased temporally with UUO, with strong epithelial expression in mitotic cells compared with controls. Apoptotic tubular epithelium showed minimal JAK3. In summary, in vitro, decreased kidney JAK3 mRNA after oxidative stress was not seen translationally. Differences in the activation of the JAK3/STAT3 pathway may have different consequences for renal fibrosis. In vivo, changes in JAK3 protein localisation, and especially its co-localisation with mitotic cells, indicate that JAK3 protein may contribute to renal tubular epithelial cell proliferation after oxidative stress.

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Mechanistic insight of diabetic nephropathy and its pharmacotherapeutic targets: An update

Cited by 216 publications

References 236 publications

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

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

Annexin A1 attenuates microvascular complications through restoration of Akt signalling in a murine model of type 1 diabetes

Role of JAK3 in the Pathogenesis of Oxidative Stress-Induced Kidney Fibrosis

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