Reduced Glomerular Filtration in Diabetes Is Attributable to Loss of Density and Increased Resistance of Glomerular Endothelial Cell Fenestrations

Finch, Natalie; Fawaz, Sarah; Neal, Chris; Butler, Matthew; Lee, Vivian; Salmon, Andrew; Lay, Abigail C; Stevens, Megan; Dalayan, Lusyan; Band, Vimla; Mellor, Harry; Harper, Steven J.; Shima, David T.; Welsh, Gavin I.; Foster, Rebecca R.; Satchell, Simon C.

doi:10.1681/asn.2021030294

Cited by 18 publications

(12 citation statements)

References 35 publications

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“…We analyzed the expression of TRPC6, LC3B, and the autophagic cargo protein sequestosome 1 (SQSTM1, also called P62) in podocytes in two murine diabetic models: ( 1 ) a type 1 diabetes mellitus model of accelerated DKD combining streptozotocin (STZ)-induced diabetes with unilateral nephrectomy 42 and ( 2 ) a type 2 diabetes model of DKD with the use of BTBR ob/ob mice. 43,44 GFP-LC3 reporter mice were used in the type 1 diabetes mellitus model to monitor the autophagic flux in vivo . 37 In both models, we demonstrated increased podocyte-specific TRPC6 expression (Figure 1, A–C).…”

Section: Resultsmentioning

confidence: 99%

Podocyte Injury in Diabetic Kidney Disease in Mouse Models Involves TRPC6-mediated Calpain Activation Impairing Autophagy

Salemkour,

Yildiz,

Dionet

et al. 2023

JASN

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Background: Diabetic kidney disease is associated with impaired podocyte autophagy and subsequent podocyte injury. The regulation of podocyte autophagy is unique, because it minimally utilizes the mTOR and AMPK pathways. Thus, the molecular mechanisms underlying the impaired autophagy in podocytes in diabetic kidney disease remain largely elusive. Methods: This study investigated how the calcium channel TRPC6 and the cysteine protease calpains deleteriously affect podocyte autophagy in diabetic kidney disease in mice. We demonstrated that TRPC6 knockdown in podocytes increased the autophagic flux due to decreased cysteine protease calpains activity. Diabetic kidney disease was induced in vivo using streptozotocin with unilateral nephrectomy in the BTBRob/ob mouse model. Results: Diabetes increased TRPC6 expression in podocytes in vivo with decreased podocyte autophagic flux. Transgenic overexpression of the endogenous calpain inhibitor calpastatin, as well as pharmacological inhibition of calpain activity, normalized podocyte autophagic flux, reduced nephrin loss, and prevented the development of albuminuria in diabetic mice. In kidney biopsies from patients with diabetes, we further confirmed that TRPC6 overexpression in podocytes correlates with decreased calpastatin expression, autophagy blockade, and podocyte injury. Conclusion: Overall, we discovered a new mechanism that connects TRPC6 and calpain activity to impaired podocyte autophagy, increased podocyte injury, and development of proteinuria in the context of diabetic kidney disease. Therefore, targeting TRPC6 and/or calpain to restore podocyte autophagy might be a promising therapeutic strategy for diabetic kidney disease.

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Section: Resultsmentioning

confidence: 99%

Podocyte Injury in Diabetic Kidney Disease in Mouse Models Involves TRPC6-mediated Calpain Activation Impairing Autophagy

Salemkour,

Yildiz,

Dionet

et al. 2023

JASN

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“…PLVAP was also detected at a later time point in the glomeruli of BTBR ob/ob mice [38]. A very recent paper impressively demonstrated induced PLVAP expression in glomerular capillaries of BTBR ob/ob mice and diabetic patients, corroborating the translational significance of PLVAP as a diagnostic marker in DKD [39]. However, it is still not clear whether PLVAP is mechanistically involved in the processes of injury or regeneration upon initial damage.…”

Section: Discussionmentioning

confidence: 97%

“…On the other hand, PLVAP is expressed in the glomerular endothelium during nephrogenesis [ 11 ], and embryonic processes operating during fetal life could generally be re-activated to repair damaged organs in adulthood. Moreover, it is known that endothelial fenestration in glomeruli is diminished early in DKD [ 19 , 39 ]. Since PLVAP is necessary for the functional and structural integrity of fenestrae [ 5 , 40 , 41 , 42 , 43 , 44 ], one may speculate that its induced expression counteracts the fenestral disintegration in the glomerular endothelium during DM.…”

Section: Discussionmentioning

confidence: 99%

PLVAP as an Early Marker of Glomerular Endothelial Damage in Mice with Diabetic Kidney Disease

Wolf

Steglich

Kessel

et al. 2023

IJMS

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Plasmalemma vesicle-associated protein (PLVAP) is the main component of endothelial diaphragms in fenestrae, caveolae, and transendothelial channels. PLVAP is expressed in the adult kidney glomerulus upon injury. Glomerular endothelial injury is associated with progressive loss of kidney function in diabetic kidney disease (DKD). This study aimed to investigate whether PLVAP could serve as a marker for glomerular endothelial damage in DKD. Glomerular PLVAP expression was analyzed in different mouse models of DKD and their respective healthy control animals using automatic digital quantification of histological whole kidney sections. Transgenic mice expressing a dominant-negative GIP receptor (GIPRdn) in pancreatic beta-cells as a model for diabetes mellitus (DM) type 1 and black and tan brachyuric (BTBR) ob/ob mice, as a model for DM type 2, were used. Distinct PLVAP induction was observed in all diabetic models studied. Traces of glomerular PLVAP expression could be identified in the healthy control kidneys using automated quantification. Stainings for other endothelial injury markers such as CD31 or the erythroblast transformation-specific related gene (ERG) displayed no differences between diabetic and healthy groups at the time points when PLVAP was induced. The same was also true for the mesangial cells marker α8Integrin, while the podocyte marker nephrin appeared to be diminished only in BTBR ob/ob mice. Glomerular hypertrophy, which is one of the initial morphological signs of diabetic kidney damage, was observed in both diabetic models. These findings suggest that PLVAP is an early marker of glomerular endothelial injury in diabetes-induced kidney damage in mice.

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“…The PLVAP protein is the main component of endothelial diaphragms in fenestrae, caveolae, and transendothelial channels, shown in previous studies to be associated with DKD and HCC. On the one hand, PLVAP can be used as an early marker of glomerular endothelial injury with DKD in mice ( 44 ), and do increase in glomeruli of human diabetic patients ( 45 ). On the other hand, PLVAP was identified as a gene expressed explicitly in HCC vascular endothelial cells ( 46 ), and has been investigated as a therapeutic target in HCC ( 46 ), perhaps based on its ability to alter the immunosuppressive microenvironment ( 47 ).…”

Section: Discussionmentioning

confidence: 99%

Screening immune-related blood biomarkers for DKD-related HCC using machine learning

Chen,

Xie,

et al. 2024

Front. Immunol.

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BackgroundDiabetes mellitus is a significant health problem worldwide, often leading to diabetic kidney disease (DKD), which may also influence the occurrence of hepatocellular carcinoma (HCC). However, the relationship and diagnostic biomarkers between DKD and HCC are unclear.MethodsUsing public database data, we screened DKD secretory RNAs and HCC essential genes by limma and WGCNA. Potential mechanisms, drugs, and biomarkers for DKD-associated HCC were identified using PPI, functional enrichment, cMAP, and machine learning algorithms, and a diagnostic nomogram was constructed. Then, ROC, calibration, and decision curves were used to evaluate the diagnostic performance of the nomograms. In addition, immune cell infiltration in HCC was explored using CIBERSORT. Finally, the detectability of critical genes in blood was verified by qPCR.Results104 DEGs associated with HCC using WGCNA were identified. 101 DEGs from DKD were predicated on secreting into the bloodstream with Exorbase datasets. PPI analysis identified three critical modules considered causative genes for DKD-associated HCC, primarily involved in inflammation and immune regulation. Using lasso and RM, four hub genes associated with DKD-associated HCC were identified, and a diagnostic nomogram confirmed by DCA curves was established. The results of immune cell infiltration showed immune dysregulation in HCC, which was associated with the expression of four essential genes. PLVAP was validated by qPCR as a possible blood-based diagnostic marker for DKD-related HCC.ConclusionWe revealed the inflammatory immune pathways of DKD-related HCC and developed a diagnostic nomogram for HCC based on PLVAP, C7, COL15A1, and MS4A6A. We confirmed with qPCR that PLVAP can be used as a blood marker to assess the risk of HCC in DKD patients.

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Reduced Glomerular Filtration in Diabetes Is Attributable to Loss of Density and Increased Resistance of Glomerular Endothelial Cell Fenestrations

Cited by 18 publications

References 35 publications

Podocyte Injury in Diabetic Kidney Disease in Mouse Models Involves TRPC6-mediated Calpain Activation Impairing Autophagy

Podocyte Injury in Diabetic Kidney Disease in Mouse Models Involves TRPC6-mediated Calpain Activation Impairing Autophagy

PLVAP as an Early Marker of Glomerular Endothelial Damage in Mice with Diabetic Kidney Disease

Screening immune-related blood biomarkers for DKD-related HCC using machine learning

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