The role of metabolic and haemodynamic factors in podocyte injury in diabetes

Stieger, Nicole; Worthmann, Kirstin; Schiffer, Mario

doi:10.1002/dmrr.1164

Cited by 44 publications

(32 citation statements)

References 108 publications

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“…10,46,47,48 Circulating metabolites, glucose levels, or, potentially, the lack of or heightened levels of adiponectin may affect this transition or injury. 49 Functional recovery or recovery of WT1+ nuclear numbers at low dimerizer doses or in the POD-Tg mouse may therefore be a return to podocyte quiescence and health. Future studies with more detailed analysis of this process through lineage tracing studies will have to address these questions in greater detail.…”

Section: Discussionmentioning

confidence: 99%

Adiponectin Promotes Functional Recovery after Podocyte Ablation

Rutkowski

Wang²,

Park

et al. 2013

Journal of the American Society of Nephrology

143

119

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Low levels of the adipocyte-secreted protein adiponectin correlate with albuminuria in both mice and humans, but whether adiponectin has a causative role in modulating renal disease is unknown. Here, we first generated a mouse model that allows induction of caspase-8-mediated apoptosis specifically in podocytes upon injection of a construct-specific agent. These POD-ATTAC mice exhibited significant kidney damage, mimicking aspects of human renal disease, such as foot process effacement, mesangial expansion, and glomerulosclerosis. After the initial induction, both podocytes and filtration function recovered. Next, we crossed POD-ATTAC mice with mice lacking or overexpressing adiponectin. POD-ATTAC mice lacking adiponectin developed irreversible albuminuria and renal failure; conversely, POD-ATTAC mice overexpressing adiponectin recovered more rapidly and exhibited less interstitial fibrosis. In conclusion, these results suggest that adiponectin is a renoprotective protein after podocyte injury. Furthermore, the POD-ATTAC mouse provides a platform for further studies, allowing precise timing of podocyte injury and regeneration.

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Section: Discussionmentioning

confidence: 99%

Adiponectin Promotes Functional Recovery after Podocyte Ablation

Rutkowski

Wang²,

Park

et al. 2013

Journal of the American Society of Nephrology

143

119

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“…Podocytes have an important role in the development of DN (29,34). These cells express all the RAS components (18,32) and are modulated in a diabetic milieu (8,9,37).…”

Section: Discussionmentioning

confidence: 99%

“…Finally, we studied podocyte cell death in the presence of insulin, as podocyte loss is one critical feature in DN (29,34). Podocytes incubated with insulin showed an evident decrease in TUNEL staining, consistent with a decrease in apoptosis, compared with the control group and both albumin groups, revealing a possible protective antiapoptotic function of insulin over these cells.…”

Section: Table 2 Gene Expression Of Ras Components In Insulin and Almentioning

confidence: 99%

“…podocytes; insulin; renin-angiotensin system; ACE2; albumin PODOCYTES ARE KEY CELLS IN the glomerular filtration barrier, and there is considerable evidence demonstrating their major role in the development of diabetic nephropathy (DN) (29,34). Previous studies have shown the presence of all the reninangiotensin system (RAS) components required for angiotensin (ANG) II production, the main effector of this system, within the podocyte (18, 32).…”

mentioning

confidence: 99%

“…However, all these effects disappeared in the presence of albumin, which may mimic albuminuria, a main feature of DN pathophysiology. Our results suggest that modulation of renin-angiotensin system balance, fibrosis, and apoptosis by insulin in the podocyte may be an important factor in preventing the development and progression of diabetic kidney disease, but the presence of albuminuria seems to block these beneficial effects.podocytes; insulin; renin-angiotensin system; ACE2; albumin PODOCYTES ARE KEY CELLS IN the glomerular filtration barrier, and there is considerable evidence demonstrating their major role in the development of diabetic nephropathy (DN) (29,34). Previous studies have shown the presence of all the reninangiotensin system (RAS) components required for angiotensin (ANG) II production, the main effector of this system, within the podocyte (18, 32).…”

mentioning

confidence: 99%

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Albumin inhibits the insulin-mediated ACE2 increase in cultured podocytes

Márquez

Riera

Pascual

et al. 2014

American Journal of Physiology-Renal Physiology

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Márquez E, Riera M, Pascual J, Soler MJ. Albumin inhibits the insulin-mediated ACE2 increase in cultured podocytes. Am J Physiol Renal Physiol 306: F1327-F1334, 2014. First published March 26, 2014 doi:10.1152/ajprenal.00594.2013.-Podocytes are key cells in the glomerular filtration barrier with a major role in the development of diabetic nephropathy. Podocytes are insulin-sensitive cells and have a functionally active local renin-angiotensin system. The presence and activity of angiotensin-converting enzyme 2 (ACE2), the main role of which is cleaving profibrotic and proinflammatory angiotensin-II into angiotensin-(1-7), have been demonstrated in podocytes. Conditionally immortalized mouse podocytes were cultured with insulin in the presence and absence of albumin. We found that insulin increases ACE2 gene and protein expression, by real-time PCR and Western blotting, respectively, and enzymatic activity within the podocyte and these increases were maintained over time. Furthermore, insulin favored an "anti-angiotensin II" regarding ACE/ACE2 gene expression balance and decreased fibronectin gene expression as a marker of fibrosis in the podocytes, all studied by real-time PCR. Similarly, insulin incubation seemed to protect podocytes from cell death, studied by a terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay. However, all these effects disappeared in the presence of albumin, which may mimic albuminuria, a main feature of DN pathophysiology. Our results suggest that modulation of renin-angiotensin system balance, fibrosis, and apoptosis by insulin in the podocyte may be an important factor in preventing the development and progression of diabetic kidney disease, but the presence of albuminuria seems to block these beneficial effects.podocytes; insulin; renin-angiotensin system; ACE2; albumin PODOCYTES ARE KEY CELLS IN the glomerular filtration barrier, and there is considerable evidence demonstrating their major role in the development of diabetic nephropathy (DN) (29,34). Previous studies have shown the presence of all the reninangiotensin system (RAS) components required for angiotensin (ANG) II production, the main effector of this system, within the podocyte (18, 32). Central elements of DN pathophysiology, such as hyperglycemia, change the expression of intrapodocyte RAS to a "pro-ANG II" profile (9, 37). One element of high interest in the RAS is angiotensin-converting enzyme 2 (ACE2), an enzyme whose main role is to cleave ANG II into ANG-(1-7) (30). Deletion of the ACE2 gene in mice leads to worsening of ANG II-induced hypertension and diabetic kidney injury (11,36). Although ACE2 expression and activity have been demonstrated in cultured podocytes (32), there are no studies in the literature focused on its variations in a diabetic state. Podocyte-specific overexpression of ACE2 transiently attenuates the development of DN in transgenic mice with streptozotocin-induced diabetes (23). Podocytes in culture are insulin-sensitive cells and are the only cells of the glomerular ...

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Increased urine podocyte‐associated messenger RNAs in severe obesity are evidence of podocyte injury

Pereira

Santos

Rodrigues

et al. 2015

Obesity

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Objective: The aim of this study was to correlate different degrees of excess weight with the expression of podocyte-associated messenger RNAs (mRNAs) in urine. Methods: The sample comprised 83 patients with overweight or obesity class I, II, or III and 18 healthy controls. The expression of nephrin, podocin, podocalyxin, a-actinin-4, a3b1integrin, vascular endothelial growth factor, and transforming growth factor-beta (TGF-b 1 ) mRNA in urine was quantified with the realtime polymerase chain reaction. mRNA expression was correlated with body mass index, the metabolic syndrome, albuminuria, and inflammation. Results: Adults with obesity class III had higher levels of serum lipids, glucose, HbA1C, insulin resistance, and C-reactive protein (P < 0.05), with 85% of the subjects meeting criteria for the metabolic syndrome (P < 0.001 vs. other groups). Urinary podocyte-associated mRNAs were higher in adults with obesity class III than in other groups (P < 0.05). Patients with overweight or obesity class I or II also had higher levels of podocyte mRNAs than controls: nephrin (P 5 0.021), a-actinin-4 (P 5 0.014), a3b1integrin (P 5 0.036), and TGF-b 1 (P 5 0.005). Metabolic syndrome, hyperinsulinemia, and C-reactive protein were correlated with podocyturia, but only higher insulin levels were related regardless of obesity. Conclusions: Severe obesity and hyperinsulinemia were associated with higher urinary expression of podocyte-associated mRNAs, even at normal urinary albumin excretion rates.

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The role of metabolic and haemodynamic factors in podocyte injury in diabetes

Cited by 44 publications

References 108 publications

Adiponectin Promotes Functional Recovery after Podocyte Ablation

Adiponectin Promotes Functional Recovery after Podocyte Ablation

Albumin inhibits the insulin-mediated ACE2 increase in cultured podocytes

Increased urine podocyte‐associated messenger RNAs in severe obesity are evidence of podocyte injury

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