Interference with Gsα-Coupled Receptor Signaling in Renin-Producing Cells Leads to Renal Endothelial Damage

Peter Lachmann, Linda Hickmann, Anne Steglich, Moath Al-Mekhlafi, Michael Gerlach, Niels Jetschin, Steffen Jahn, Brigitte Hamann, Monika Wnuk, Kirsten Madsen, Valentin Djonov, Min Chen, Lee S Weinstein, Bernd Hohenstein, Christian P M Hugo, Vladimir T Todorov

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Intracellular cAMP, the production of which is catalyzed by the α-subunit of the stimulatory G protein (Gsα), controls renin synthesis and release by juxtaglomerular (JG) cells of the kidney, but may also have relevance for the physiologic integrity of the kidney. To investigate this possibility, we generated mice with inducible knockout of Gsα in JG cells and monitored them for 6 months after induction at 6 weeks of age. The knockout mapped exclusively to the JG cells of the Gsα-deficient animals. Progressive albuminuria occurred in Gsα-deficient mice. Compared with controls expressing wild-type Gsα alleles, the Gsα-deficient mice had enlarged glomeruli with mesangial expansion, injury, and FSGS at study end. Ultrastructurally, the glomerular filtration barrier of the Gsα-deficient animals featured endothelial gaps, thickened basement membrane, and fibrin-like intraluminal deposits, which are classic signs of thrombotic microangiopathy. Additionally, we found endothelial damage in peritubular capillaries and vasa recta. Because deficiency of vascular endothelial growth factor (VEGF) results in thrombotic microangiopathy, we addressed the possibility that Gsα knockout may result in impaired VEGF production. We detected VEGF expression in JG cells of control mice, and cAMP agonists regulated VEGF expression in cultured renin-producing cells. Our data demonstrate that Gsα deficiency in JG cells of adult mice results in kidney injury, and suggest that JG cells are critically involved in the maintenance and protection of the renal microvascular endothelium.

OriginalsprogEngelsk
TidsskriftJournal of the American Society of Nephrology
Vol/bind28
Udgave nummer12
Sider (fra-til)3479–3489
ISSN1046-6673
DOI
StatusUdgivet - 2017

Fingeraftryk

Renin
Kidney
Vascular Endothelial Growth Factor A
Gs GTP-Binding Protein alpha Subunits
Albuminuria
Wounds and Injuries
Rectum
Endothelium
Alleles
Maintenance

Citer dette

Lachmann, P., Hickmann, L., Steglich, A., Al-Mekhlafi, M., Gerlach, M., Jetschin, N., ... Todorov, V. T. (2017). Interference with Gsα-Coupled Receptor Signaling in Renin-Producing Cells Leads to Renal Endothelial Damage. Journal of the American Society of Nephrology, 28(12), 3479–3489. https://doi.org/10.1681/ASN.2017020173
Lachmann, Peter ; Hickmann, Linda ; Steglich, Anne ; Al-Mekhlafi, Moath ; Gerlach, Michael ; Jetschin, Niels ; Jahn, Steffen ; Hamann, Brigitte ; Wnuk, Monika ; Madsen, Kirsten ; Djonov, Valentin ; Chen, Min ; Weinstein, Lee S ; Hohenstein, Bernd ; Hugo, Christian P M ; Todorov, Vladimir T. / Interference with Gsα-Coupled Receptor Signaling in Renin-Producing Cells Leads to Renal Endothelial Damage. I: Journal of the American Society of Nephrology. 2017 ; Bind 28, Nr. 12. s. 3479–3489.
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abstract = "Intracellular cAMP, the production of which is catalyzed by the α-subunit of the stimulatory G protein (Gsα), controls renin synthesis and release by juxtaglomerular (JG) cells of the kidney, but may also have relevance for the physiologic integrity of the kidney. To investigate this possibility, we generated mice with inducible knockout of Gsα in JG cells and monitored them for 6 months after induction at 6 weeks of age. The knockout mapped exclusively to the JG cells of the Gsα-deficient animals. Progressive albuminuria occurred in Gsα-deficient mice. Compared with controls expressing wild-type Gsα alleles, the Gsα-deficient mice had enlarged glomeruli with mesangial expansion, injury, and FSGS at study end. Ultrastructurally, the glomerular filtration barrier of the Gsα-deficient animals featured endothelial gaps, thickened basement membrane, and fibrin-like intraluminal deposits, which are classic signs of thrombotic microangiopathy. Additionally, we found endothelial damage in peritubular capillaries and vasa recta. Because deficiency of vascular endothelial growth factor (VEGF) results in thrombotic microangiopathy, we addressed the possibility that Gsα knockout may result in impaired VEGF production. We detected VEGF expression in JG cells of control mice, and cAMP agonists regulated VEGF expression in cultured renin-producing cells. Our data demonstrate that Gsα deficiency in JG cells of adult mice results in kidney injury, and suggest that JG cells are critically involved in the maintenance and protection of the renal microvascular endothelium.",
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Lachmann, P, Hickmann, L, Steglich, A, Al-Mekhlafi, M, Gerlach, M, Jetschin, N, Jahn, S, Hamann, B, Wnuk, M, Madsen, K, Djonov, V, Chen, M, Weinstein, LS, Hohenstein, B, Hugo, CPM & Todorov, VT 2017, 'Interference with Gsα-Coupled Receptor Signaling in Renin-Producing Cells Leads to Renal Endothelial Damage', Journal of the American Society of Nephrology, bind 28, nr. 12, s. 3479–3489. https://doi.org/10.1681/ASN.2017020173

Interference with Gsα-Coupled Receptor Signaling in Renin-Producing Cells Leads to Renal Endothelial Damage. / Lachmann, Peter; Hickmann, Linda; Steglich, Anne; Al-Mekhlafi, Moath; Gerlach, Michael; Jetschin, Niels; Jahn, Steffen; Hamann, Brigitte; Wnuk, Monika; Madsen, Kirsten; Djonov, Valentin; Chen, Min; Weinstein, Lee S; Hohenstein, Bernd; Hugo, Christian P M; Todorov, Vladimir T.

I: Journal of the American Society of Nephrology, Bind 28, Nr. 12, 2017, s. 3479–3489.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Interference with Gsα-Coupled Receptor Signaling in Renin-Producing Cells Leads to Renal Endothelial Damage

AU - Lachmann, Peter

AU - Hickmann, Linda

AU - Steglich, Anne

AU - Al-Mekhlafi, Moath

AU - Gerlach, Michael

AU - Jetschin, Niels

AU - Jahn, Steffen

AU - Hamann, Brigitte

AU - Wnuk, Monika

AU - Madsen, Kirsten

AU - Djonov, Valentin

AU - Chen, Min

AU - Weinstein, Lee S

AU - Hohenstein, Bernd

AU - Hugo, Christian P M

AU - Todorov, Vladimir T

N1 - Copyright © 2017 by the American Society of Nephrology.

PY - 2017

Y1 - 2017

N2 - Intracellular cAMP, the production of which is catalyzed by the α-subunit of the stimulatory G protein (Gsα), controls renin synthesis and release by juxtaglomerular (JG) cells of the kidney, but may also have relevance for the physiologic integrity of the kidney. To investigate this possibility, we generated mice with inducible knockout of Gsα in JG cells and monitored them for 6 months after induction at 6 weeks of age. The knockout mapped exclusively to the JG cells of the Gsα-deficient animals. Progressive albuminuria occurred in Gsα-deficient mice. Compared with controls expressing wild-type Gsα alleles, the Gsα-deficient mice had enlarged glomeruli with mesangial expansion, injury, and FSGS at study end. Ultrastructurally, the glomerular filtration barrier of the Gsα-deficient animals featured endothelial gaps, thickened basement membrane, and fibrin-like intraluminal deposits, which are classic signs of thrombotic microangiopathy. Additionally, we found endothelial damage in peritubular capillaries and vasa recta. Because deficiency of vascular endothelial growth factor (VEGF) results in thrombotic microangiopathy, we addressed the possibility that Gsα knockout may result in impaired VEGF production. We detected VEGF expression in JG cells of control mice, and cAMP agonists regulated VEGF expression in cultured renin-producing cells. Our data demonstrate that Gsα deficiency in JG cells of adult mice results in kidney injury, and suggest that JG cells are critically involved in the maintenance and protection of the renal microvascular endothelium.

AB - Intracellular cAMP, the production of which is catalyzed by the α-subunit of the stimulatory G protein (Gsα), controls renin synthesis and release by juxtaglomerular (JG) cells of the kidney, but may also have relevance for the physiologic integrity of the kidney. To investigate this possibility, we generated mice with inducible knockout of Gsα in JG cells and monitored them for 6 months after induction at 6 weeks of age. The knockout mapped exclusively to the JG cells of the Gsα-deficient animals. Progressive albuminuria occurred in Gsα-deficient mice. Compared with controls expressing wild-type Gsα alleles, the Gsα-deficient mice had enlarged glomeruli with mesangial expansion, injury, and FSGS at study end. Ultrastructurally, the glomerular filtration barrier of the Gsα-deficient animals featured endothelial gaps, thickened basement membrane, and fibrin-like intraluminal deposits, which are classic signs of thrombotic microangiopathy. Additionally, we found endothelial damage in peritubular capillaries and vasa recta. Because deficiency of vascular endothelial growth factor (VEGF) results in thrombotic microangiopathy, we addressed the possibility that Gsα knockout may result in impaired VEGF production. We detected VEGF expression in JG cells of control mice, and cAMP agonists regulated VEGF expression in cultured renin-producing cells. Our data demonstrate that Gsα deficiency in JG cells of adult mice results in kidney injury, and suggest that JG cells are critically involved in the maintenance and protection of the renal microvascular endothelium.

KW - Journal Article

U2 - 10.1681/ASN.2017020173

DO - 10.1681/ASN.2017020173

M3 - Journal article

C2 - 28775003

VL - 28

SP - 3479

EP - 3489

JO - Journal of the American Society of Nephrology

JF - Journal of the American Society of Nephrology

SN - 1046-6673

IS - 12

ER -