Renin cells with defective Gsα/cAMP signaling contribute to renal endothelial damage

Steglich, Anne; Kessel, Friederike; Hickmann, Linda; Gerlach, Michael; Lachmann, P. J.; Gembardt, Florian; Lesche, Mathias; Dahl, Andreas; Federlein, Anna; Schweda, Frank; Hugo, Christian; Todorov, Vladimir

doi:10.1007/s00424-019-02298-9

Cited by 9 publications

(9 citation statements)

References 62 publications

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“…The strong expression of PLVAP was observed in the glomeruli of transgenic mouse strains representing well-described and generally accepted models for DM type 1 and type 2 [22][23][24][25][26]. These results fit the current paradigm postulating that PLVAP production is induced in diseased glomeruli [10][11][12]. Our findings are also in line with an earlier study reporting the induction of glomerular PLVAP expression in diabetic BMP and Activin Membrane-Bound Inhibitor (BAMBI)-deficient mice [37].…”

Section: Discussionsupporting

confidence: 91%

“…We here report on PLVAP as an early glomerular-specific histological marker of microendothelial damage in different diabetic mouse models. PLVAP is expressed in the glomerular endothelium after injury [ 10 , 11 , 12 ]. In contrast to some reports [ 5 , 10 , 11 ], we found traces of PLVAP protein in the glomeruli of healthy mice by using an unbiased automatic quantification of whole histological kidney sections.…”

Section: Discussionmentioning

confidence: 99%

“…In glomerular capillaries, PLVAP is absent because the glomerular endothelium lacks diaphragms in their fenestrae [ 5 ]. However, glomerular expression of PLVAP has been reported in models of renal endothelial injury such as transplant glomerulopathy, Thy-1.1 glomerulonephritis, and thrombotic microangiopathy in mice with defective Gsα/cAMP signaling in renin cells [ 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…The importance of the ubiquitously expressed Gsα in the maintenance of normal functions in divergent organs had been demonstrated in many studies using tissue-specific Gsα transgenic and knockout mouse models ( 18 – 21 ). The indispensable role of Gsα in the control of vascular development was indicated by the fact that germline endothelia-specific Gsα deficiency led to embryonic lethality due to massive hemorrhage and a disorganized vasculature ( 8 ).…”

Section: Discussionmentioning

confidence: 99%

Endothelial G protein stimulatory α-subunit is a critical regulator of post-ischemic angiogenesis

Lu²,

Chu³

et al. 2022

Front. Cardiovasc. Med.

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Post-ischemic angiogenesis is a vital pathophysiological process in diseases such as peripheral arterial disease (PAD), heart ischemia, and diabetic retinopathy. The molecular mechanisms of post-ischemic angiogenesis are complicated and not fully elucidated. The G protein stimulatory alpha subunit (Gsα) is essential for hormone-stimulated cyclic adenosine monophosphate (cAMP) production and is an important regulator for many physiological processes. In the present study, we investigated the role of endothelial Gsα in post-ischemic angiogenesis by generating adult mice with endothelial-specific Gsα deficiency (GsαECKO). GsαECKO mice had impaired blood flow recovery after hind limb ischemic injury, and reduced neovascularization in allograft transplanted tumors. Mechanically, Gsα could regulate the expression of angiogenic factor with G patch and FHA domains 1 (AGGF1) through cAMP/CREB pathway. AGGF1 plays a key role in angiogenesis and regulates endothelial cell proliferation as well as migration. Knockdown of CREB or mutation of the CRE site on the AGGF1 promoter led to reduced AGGF1 promoter activity. In addition, knockdown of AGGF1 reduced the proangiogenic effect of Gsα in endothelial cells, and overexpression of AGGF1 reversed the impaired angiogenesis in GsαECKO mice in vivo. The finding may prove useful in designing new therapeutic targets for treatments of post-ischemic angiogenesis-related diseases.

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“…Eight-week-old female mRen-rtTAm2/LC-1/tdT mice underwent pulse induction via recombination with 625 mg/kg Doxycycline and 10 mg/kg enalapril for 21 days, followed by 7 days of washout without Doxycycline and enalapril (see Figure 1A ) and were then used for imaging of healthy and laser-injured glomeruli ( Ashworth et al, 2007 ; Steglich et al, 2019 ). Female mice are smaller compared to males and the nephrons are thus closer to the renal capsule ( Schiessl et al, 2013 ).…”

Section: Methodsmentioning

confidence: 99%

A quantitative 3D intravital look at the juxtaglomerular renin-cell-niche reveals an individual intra/extraglomerular feedback system

Arndt

Sradnick²,

Kröger³

et al. 2022

Front. Physiol.

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The juxtaglomerular niche occupied by renin cells (RCN) plays an important role in glomerular repair but the precise temporal and spatial interrelations remain unclear. This study proposes the hypothesis of a local intra-extraglomerular regenerative feedback system and establishes a new quantifiable system for RCN responses in individual glomeruli in vivo. A strictly intraglomerular two-photon laser-induced injury model was established. Labeled renin cells (RC) in transgenic renin reporter mice were fate-traced in healthy and injured glomeruli over several days by intravital microscopy and quantified via new three-dimensional image processing algorithms based on ray tracing. RC in healthy glomeruli demonstrated dynamic extraglomerular protrusions. Upon intraglomerular injury the corresponding RCN first increased in volume and then increased in area of dynamic migration up to threefold compared to their RCN. RC started migration reaching the site of injury within 3 hours and acquired a mesangial cell phenotype without losing physical RCN-contact. During intraglomerular repair only the corresponding RCN responded via stimulated neogenesis, a process of de novo differentiation of RC to replenish the RCN. Repeated continuous intravital microscopy provides a state-of-the-art tool to prove and further study the local intraglomerular RCN repair feedback system in individual glomeruli in vivo in a quantifiable manner.

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Renin cells with defective Gsα/cAMP signaling contribute to renal endothelial damage

Cited by 9 publications

References 62 publications

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

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

Endothelial G protein stimulatory α-subunit is a critical regulator of post-ischemic angiogenesis

A quantitative 3D intravital look at the juxtaglomerular renin-cell-niche reveals an individual intra/extraglomerular feedback system

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