New targets for treatment of diabetic nephropathy

Brosius, Frank C.; Alpers, Charles E.

doi:10.1097/mnh.0b013e32835b3766

Cited by 42 publications

(38 citation statements)

References 36 publications

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“…We then utilized Nephroseq, an online database that is part of the University of Michigan NIDDK O’Brien Kidney Center (www.nephroseq.org) to interrogate an independent transcriptomic dataset of human DKD subjects with reduced eGFR (~25–35 mL/min) published by other investigators 20 . We found similar increases in tubulointerstitial expression of JAK1, JAK2, STAT1 and STAT3 genes in this set of 22 patients with progressive DKD 21 . The increases in JAK-STAT gene expression were not found in several mouse models of DKD even though there was evidence of glomerular JAK-STAT activation in the mice 3, 4 .…”

Section: Discussionsupporting

confidence: 71%

Podocyte-specific JAK2 overexpression worsens diabetic kidney disease in mice

Zhang

Nair

Saha

et al. 2017

Kidney International

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Activation of the JAK-STAT signaling has been implicated in the pathogenesis of diabetic kidney disease. An increased expression of JAK-STAT genes was found in kidney glomerular cells, including podocytes, in patients with early diabetic kidney disease. However, it is not known whether increased expression of JAK or STAT isoforms in glomerular cells can lead to worsening nephropathy in the setting of diabetes. Therefore, we overexpressed JAK2 mRNA specifically in glomerular podocytes of 129S6 mice to determine whether this change alone could worsen diabetic kidney disease. A 2–3 fold increase in glomerular JAK2 expression, an increase similar to that found in humans with early diabetic kidney disease, led to substantial and statistically significant increases in albuminuria, mesangial expansion, glomerulosclerosis, glomerular fibronectin accumulation, and glomerular basement membrane thickening, and a significant reduction in podocyte density in diabetic mice. Treatment with a specific JAK1/2 inhibitor for 2 weeks partly reversed the major phenotypic changes of diabetic kidney disease and specifically normalized expression of a number of downstream STAT3-dependent genes implicated in diabetic kidney disease progression. Thus, moderate increases in podocyte JAK2 expression at levels similar to those in patients with early diabetic kidney disease can lead directly to phenotypic and other alterations of progressive diabetic glomerulopathy. Hence, inhibition of these changes by treatment with a JAK1/2 inhibitor suggests that such treatment may help retard progression of early diabetic kidney disease in patients.

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Section: Discussionsupporting

confidence: 71%

Podocyte-specific JAK2 overexpression worsens diabetic kidney disease in mice

Zhang

Nair

Saha

et al. 2017

Kidney International

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“…Furthermore, much of this information has been made freely available to the nephrology community through web-based interfaces such as Nephromine (www.nephromine.org). Researchers are now employing similar techniques to assess whether key pathways activated in human DN are similarly induced in rodent models [3]. …”

Section: Use Of Transcriptomic Profiling To Compare Pathways Activatementioning

confidence: 99%

“…Animal models may be useful in dissecting the pathogenesis of the disease and for testing novel therapies. However, their utility in DN research has been constrained by the fact that most models fail to recapitulate important functional and structural features of advanced human disease [2,3]. This may partly explain why therapies that have shown benefit in animal models have often proven less effective in human DN.…”

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confidence: 99%

Recent Advances in Animal Models of Diabetic Nephropathy

Betz

Conway

2014

Nephron Exp Nephrol

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Diabetic nephropathy (DN) is the single most common cause of end-stage kidney disease. Therefore, it is imperative that novel therapies are developed. Progress has been hindered, however, by the lack of robust animal models. In the current review we describe recent advances in the field, including the impact of background strain, hypertension and transcriptomic profiling. While the C57BL/6J strain is relatively resistant to DN, the FVB strain appears more susceptible and Ove26 and db/db mice on this background may be useful in modelling types 1 and 2 DN, respectively. Black and tan, brachyury (BTBR) mice deficient for the leptin receptor (ob/ob) develop many of the pathological features of human DN and, remarkably, treatment with exogenous leptin ameliorates hyperglycaemia, albuminuria and glomerulosclerosis. Hypertension plays a key role in the progression of human DN and exacerbates nephropathy in diabetic rodents. Endothelial nitric oxide synthase deficiency (eNOS^-/-) results in moderate hypertension and the development of nodular glomerulosclerosis and hyaline arteriosclerosis in streptozotocin-induced diabetic C57BL/6J mice. In Cyp1a1mRen2 rats, renin-dependent hypertension synergises with streptozotocin-induced hyperglycaemia to produce a 500-fold increase in albuminuria, glomerulosclerosis and tubulointerstitial fibrosis. Renal transcriptional profiling suggests that many of the gene expression changes observed in human DN are replicated in eNOS^-/- mice and Cyp1a1mRen2 rats. Despite these advances, no model faithfully recapitulates all the features of human DN and further refinements are required. In the interim, it is likely that researchers may use publically available transcriptomic data to select the most appropriate model to study their molecule or pathway of interest.

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“…Albuminuria, a common characteristic of DN, is associated with a higher incidence of progression toward renal failure [1]; therefore, reducing urine albumin is an important goal toward preventing renal functional decline [2]. To date, there remains no completely effective approach to prevent the development and/or progression of DN in diabetic patients.…”

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confidence: 99%

Renal improvement by zinc in diabetic mice is associated with glucose metabolism signaling mediated by metallothionein and Akt, but not Akt2

Sun

Wang

Miao

et al. 2014

Free Radical Biology and Medicine

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Human epidemiological and animal studies have shown the beneficial effect of zinc supplementation on mitigating diabetic nephropathy. However, the mechanism by which zinc protects the kidney from diabetes remains unknown. Here we demonstrate the therapeutic effects of zinc on diabetes-induced renal pathological and functional changes. These abnormalities were found in both transgenic OVE26 and Akt2-KO diabetic mouse models, accompanied by significant changes in glucose-metabolism-related regulators. The changes included significantly decreased phosphorylation of Akt and GSK-3β, increased phosphorylation of renal glycogen synthase, decreased expression of hexokinase II and PGC-1α, and increased expression of the Akt negative regulators PTEN, PTP1B, and TRB3. All of these were significantly prevented by zinc treatment for 3 months. Furthermore, zinc-stimulated changes in glucose metabolism mediated by Akt were actually found to be metallothionein dependent, but not Akt2 dependent. These results suggest that the therapeutic effects of zinc in diabetic nephropathy are mediated, in part, by the preservation of glucose-metabolism-related pathways via the prevention of diabetes-induced upregulation of Akt negative regulators. Given that zinc deficiency is very common in diabetics, this finding implies that regularly monitoring zinc levels in diabetic patients, as well as supplementing if low, is important in mitigating the development of diabetic nephropathy.

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New targets for treatment of diabetic nephropathy

Cited by 42 publications

References 36 publications

Podocyte-specific JAK2 overexpression worsens diabetic kidney disease in mice

Podocyte-specific JAK2 overexpression worsens diabetic kidney disease in mice

Recent Advances in Animal Models of Diabetic Nephropathy

Renal improvement by zinc in diabetic mice is associated with glucose metabolism signaling mediated by metallothionein and Akt, but not Akt2

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