Nephrogenic diabetes insipidus in mice lacking all nitric oxide synthase isoforms

Morishita, Tsuyoshi; Tsutsui, Masato; Shimokawa, Hiroaki; Sabanai, Ken; Tasaki, Hiromi; Suda, Osamu; Nakata, Shuhei; Tanimoto, Akihide; Wang, Ke-Yong; Ueta, Yoichi; Sasaguri, Yasuyuki; Nakashima, Yasuhide; Yanagihara, Nobuyuki

doi:10.1073/pnas.0502236102

Cited by 140 publications

(139 citation statements)

References 45 publications

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“…Even animals defi cient for all 3 NOS isoforms may survive to adulthood (although hypertensive, infertile, and with nephrogenic diabetes insipidus) [ 31 ]. Our results provide a partial explanation for this phenomenon.…”

Section: Or 10mentioning

confidence: 48%

Role of Nitric Oxide Signaling in Endothelial Differentiation of Embryonic Stem Cells

Huang

Fleißner

Sun

et al. 2010

Stem Cells and Development

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Signaling pathways that govern embryonic stem cell (ESCs) differentiation are not well characterized. Nitric oxide (NO) is a potent vasodilator that modulates other signaling pathways in part by activating soluble guanylyl cyclase (sGC) to produce cyclic guanosine monophosphate (cGMP). Because of its importance in endothelial cell (EC) growth in the adult, we hypothesized that NO may play a critical role in EC development. Accordingly, we assessed the role of NO in ESC differentiation into ECs. Murine ESCs differentiated in the presence of NO synthase (NOS) inhibitor NG-nitroarginine methyl ester ( l -NAME) for up to 11 days were not signifi cantly different from vehicle-treated cells in EC markers. However, by 14 days, l -NAME-treated cells manifested modest reduction in EC markers CD144, FLK1, and endothelial NOS. ESC-derived ECs generated in the presence of l -NAME exhibited reduced tube-like formation in Matrigel. To understand the discrepancy between early and late effects of l -NAME, we assessed the NOS machinery and observed low mRNA expression of NOS and sGC subunits in ESCs, compared to differentiating cells after 14 days. In response to NO donors or activation of NOS or sGC, cellular cGMP levels were undetectable in undifferentiated ESCs, at low levels on day 7, and robustly increased in day 14 cells. Production of cGMP upon NOS activation at day 14 was inhibited by l -NAME, confi rming endogenous NO dependence. Our data suggest that NOS elements are present in ESCs but inactive until later stages of differentiation, during which period NOS inhibition reduces expression of EC markers and impairs angiogenic function.

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Section: Or 10mentioning

confidence: 48%

Role of Nitric Oxide Signaling in Endothelial Differentiation of Embryonic Stem Cells

Huang

Fleißner

Sun

et al. 2010

Stem Cells and Development

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“…15,16 Interestingly, several other mouse models in which polyuria is associated with perturbations in renal structure are reported to have greatly reduced AQP2 expression, whereas polyuric models with no structural abnormalities have normal AQP2 levels. 14,[17][18][19][20][21][22] Thus, we hypothesized that the tubular abnormalities seen in the neonatal AQP2 knockout animals and/or AQP2 transgenics are due to an intrinsic defect associated with the absence or dysfunction of AQP2 rather than being a secondary effect of polyuria.…”

mentioning

confidence: 99%

Aquaporin 2 Promotes Cell Migration and Epithelial Morphogenesis

Chen

Rice

et al. 2012

Journal of the American Society of Nephrology

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The aquaporin 2 (AQP2) water channel, expressed in kidney collecting ducts, contributes critically to water homeostasis in mammals. Animals lacking or having significantly reduced levels of AQP2, however, have not only urinary concentrating abnormalities but also renal tubular defects that lead to neonatal mortality from renal failure. Here, we show that AQP2 is not only a water channel but also an integrin-binding membrane protein that promotes cell migration and epithelial morphogenesis. AQP2 expression modulates the trafficking and internalization of integrin b1, facilitating its turnover at focal adhesions. In vitro, disturbing the interaction between AQP2 and integrin b1 by mutating the RGD motif led to reduced endocytosis, retention of integrin b1 at the cell surface, and defective cell migration and tubulogenesis. Similarly, in vivo, AQP2-null mice exhibited significant retention of integrin b1 at the basolateral membrane and had tubular abnormalities. In summary, these data suggest that the water channel AQP2 interacts with integrins to promote renal epithelial cell migration, contributing to the structural and functional integrity of the mammalian kidney. Aquaporin 2 (AQP2) is a water channel that mediates water absorption through the apical membrane of the principal cells of the kidney collecting ducts, and contributes critically to water homeostasis in mammals. Under physiologic conditions, the trafficking of AQP2 is regulated mainly by vasopressin via a well established signaling pathway that results in the elevation of cAMP, activation of protein kinase A (PKA) and phosphorylation of AQP2. [1][2][3] In addition to regulated trafficking, AQP2 also constitutively recycles between intracellular vesicles and the cell membrane. 4,5 Critical protein/protein interactions that orchestrate the regulated and constitutive trafficking of AQP2 have been extensively investigated and include actin and microtubules, SNAREs, Rab proteins, heat shock protein 70, clathrin, and others. 6-9 However, emerging data from AQP2 knockout and transgenic animals suggested an unusual aspect of AQP2 biology. As expected, induction of AQP2 deficiency in mice results in a urinary concentrating defect known as diabetes insipidus (DI). However, these animals also presented with neonatal mortality from renal failure with renal tubular abnormalities. [10][11][12] This striking phenotype was thought to result from their profound polyuria. However, mice

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“…45 Triple KO mice lacking nNOS, iNOS, and eNOS have impaired renal cyclic adenosine monophosphate production and aquaporin-2 expression, resulting in nephrogenic diabetes insipidus-like phenotype, with no apparent glomerular disease. 46,47 These discrepancies underscore the intriguing possibility that alternative sources of NO (nonenzymatic) may have pathogenic effects, warranting further studies.…”

Section: Discussionmentioning

confidence: 99%

Podocyte-Specific VEGF-A Gain of Function Induces Nodular Glomerulosclerosis in eNOS Null Mice

Verón

Aggarwal

Velázquez³

et al. 2014

Journal of the American Society of Nephrology

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VEGF-A and nitric oxide are essential for glomerular filtration barrier homeostasis and are dysregulated in diabetic nephropathy. Here, we examined the effect of excess podocyte VEGF-A on the renal phenotype of endothelial nitric oxide synthase (eNOS) knockout mice. Podocyte-specific VEGF 164 gain of function in eNOS 2/2 mice resulted in nodular glomerulosclerosis, mesangiolysis, microaneurysms, and arteriolar hyalinosis associated with massive proteinuria and renal failure in the absence of diabetic milieu or hypertension. In contrast, podocyte-specific VEGF 164 gain of function in wild-type mice resulted in less pronounced albuminuria and increased creatinine clearance. Transmission electron microscopy revealed glomerular basement membrane thickening and podocyte effacement in eNOS 2/2 mice with podocytespecific VEGF 164 gain of function. Furthermore, glomerular nodules overexpressed collagen IV and laminin extensively. Biotin-switch and proximity ligation assays demonstrated that podocyte-specific VEGF 164 gain of function decreased glomerular S-nitrosylation of laminin in eNOS 2/2 mice. In addition, treatment with VEGF-A decreased S-nitrosylated laminin in cultured podocytes. Collectively, these data indicate that excess glomerular VEGF-A and eNOS deficiency is necessary and sufficient to induce Kimmelstiel-Wilsonlike nodular glomerulosclerosis in mice through a process that involves deposition of laminin and collagen IV and de-nitrosylation of laminin.

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Nephrogenic diabetes insipidus in mice lacking all nitric oxide synthase isoforms

Cited by 140 publications

References 45 publications

Role of Nitric Oxide Signaling in Endothelial Differentiation of Embryonic Stem Cells

Role of Nitric Oxide Signaling in Endothelial Differentiation of Embryonic Stem Cells

Aquaporin 2 Promotes Cell Migration and Epithelial Morphogenesis

Podocyte-Specific VEGF-A Gain of Function Induces Nodular Glomerulosclerosis in eNOS Null Mice

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