Drug and Diabetic Nephropathy

Rani, Rozina

doi:10.5772/36769

Cited by 2 publications

(4 citation statements)

References 127 publications

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“…Taken together, these findings indicate that YAP/TAZ hyperactivation in PDGFRβ + MCs induces their abnormal proliferation and dedifferentiation into myofibroblast-like cells, along with glomerular fibrosis, the common pathologic features of DN. 11,13…”

Section: Resultsmentioning

confidence: 99%

“…This animal model faithfully recapitulates the glomerular impairment of DN. 11,13 Of note, the primary pathologic alterations in MCs induced by hyperactivation of YAP/TAZ seemed to cause secondary pathologic alterations in glomerular ECs, implying that MCs could be a primary and direct target in DN pathogenesis. Our genetic analysis revealed that YAP/TAZ hyperactivation in PDGFRβ + MCs induces glomerular pathologic alterations mediated through a canonical Hippo pathway.…”

Section: Discussionmentioning

confidence: 99%

“…8,10 These alterations in MCs are critically involved in reduced renal function in diabetic nephropathy (DN). 11–13 Continuous exposure to high blood glucose elicits structural and functional alterations in glomerular ECs and MCs, including disrupted EC fenestrations, MC proliferation, excessive accumulation of extracellular matrix (ECM) around MCs, and reduced glomerular filtration. 12,13 Nevertheless, an exact and detailed underlying molecular mechanism for how high blood glucose induces these alterations has yet to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Hyperactivation of YAP/TAZ Drives Alterations in Mesangial Cells through Stabilization of N-Myc in Diabetic Nephropathy

Choi

Hong

Bae

et al. 2023

JASN

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Significance Statement Mesangial cells (MCs) in the kidney are essential to maintaining glomerular integrity, and their impairment leads to major glomerular diseases including diabetic nephropathy (DN). Although high blood glucose elicits abnormal alterations in MCs, the underlying mechanism is poorly understood. We show that YAP/TAZ are increased in MCs of patients with DN and two animal models of DN. High glucose directly induces activation of YAP/TAZ through the canonical Hippo pathway in cultured MCs. Hyperactivation of YAP/TAZ in mouse MCs recapitulates the hallmarks of DN. Activated YAP/TAZ bind and stabilize N-Myc, one of the Myc family. N-Myc stabilization leads to aberrant enhancement of its transcriptional activity and to MC impairments. Our findings shed light on how high blood glucose in diabetes mellitus leads to DN and support a rationale that lowering blood glucose in diabetes mellitus could delay DN pathogenesis. Background Mesangial cells (MCs) in the kidney are central to maintaining glomerular integrity, and their impairment leads to major glomerular diseases, including diabetic nephropathy (DN). Although high blood glucose elicits abnormal alterations in MCs, the underlying molecular mechanism is poorly understood. Methods Immunolocalization of YAP/TAZ and pathological features of PDGFRβ+ MCs were analyzed in the glomeruli of patients with DN, in Zucker diabetic fatty rats, and in Lats1/2 iΔPβ mice. RiboTag bulk-RNA sequencing and transcriptomic analysis of gene expression profiles of the isolated MCs from control and Lats1/2 iΔPβ mice were performed. Immunoprecipitation analysis and protein stability of N-Myc were performed by the standard protocols. Results YAP and TAZ, the final effectors of the Hippo pathway, are highly increased in MCs of patients with DN and in Zucker diabetic fatty rats. Moreover, high glucose directly induces activation of YAP/TAZ through the canonical Hippo pathway in cultured MCs. Hyperactivation of YAP/TAZ in mouse model MCs recapitulates the hallmarks of DN, including excessive proliferation of MCs and extracellular matrix deposition, endothelial cell impairment, glomerular sclerosis, albuminuria, and reduced glomerular filtration rate. Mechanistically, activated YAP/TAZ bind and stabilize N-Myc protein, one of the Myc family of oncogenes. N-Myc stabilization leads to aberrant enhancement of its transcriptional activity and eventually to MC impairments and DN pathogenesis. Conclusions Our findings shed light on how high blood glucose in diabetes mellitus leads to DN and support a rationale that lowering blood glucose in diabetes mellitus could delay DN pathogenesis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hyperactivation of YAP/TAZ Drives Alterations in Mesangial Cells through Stabilization of N-Myc in Diabetic Nephropathy

Choi

Hong

Bae

et al. 2023

JASN

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“…7 Most of the identified physiological effects of Ang II are caused by AT1R and are widely distributed in most organs, including the heart, liver, brain, lung, kidney, adrenals and vasculature, 8 including induction of growth, vasoconstriction, secretion of aldosterone, antinatriuresis, inhibition of the biosynthesis of renin and sympathetic outflow. 9 AT2R is also believed to be related to the development of fetal organs. Subsequently, AT2R is found in large amounts in fetal tissues.…”

Section: Introductionmentioning

confidence: 99%

Angiotensin II type 2 receptor gene polymorphisms and serum angiotensin-converting enzyme level in Egyptian children with systemic lupus erythematosus

Shoaib

Yahia

Elsaid

et al. 2019

Lupus

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Background There are no reports about the association of angiotensin II type 2 receptor (AT2R) gene polymorphisms and susceptibility to systemic lupus erythematosus (SLE) in children. Objective The objective of this research is to study AT2R gene polymorphisms in exon 3 (C1593A) and intron 1 (A1675G) in Egyptian children with SLE and its correlation with disease manifestations and serum angiotensin-converting enzyme (ACE) level. Methods Typing of AT2R gene polymorphisms was conducted in 123 children with SLE in comparison with 100 healthy controls using the restriction fragment length polymorphism method. Results Significant differences were found between SLE patients and controls for A-containing genotypes (CA + AA) and A-allele frequencies of AT2R in exon 3 (C1593A) (p = 0.01, odds ratio (OR) = 2.5, 95% confidence interval (CI) = 1.3–5.05; p = 0.01, OR = 2.2, 95% CI = 1.2–4.1, respectively). G-containing genotypes (AG + GG) and G allele of AT2R in intron 1 (A1675G) were more frequent in SLE patients compared to controls (p = 0.01, OR = 2.3, 95% CI = 1.2–4.5; p = 0.02, OR = 2.1, 95% CI = 1.2–3.7, respectively). Serum ACE level was significantly higher in SLE patients than in controls (p < 0.001). There was no association between AT2R gene polymorphisms and ACE level in serum. Moreover, there was no association between AT2R gene polymorphisms and SLE clinical manifestations. Conclusion AT2R gene polymorphisms can be considered risk factors for SLE development in Egyptian children.

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Drug and Diabetic Nephropathy

Cited by 2 publications

References 127 publications

Hyperactivation of YAP/TAZ Drives Alterations in Mesangial Cells through Stabilization of N-Myc in Diabetic Nephropathy

Hyperactivation of YAP/TAZ Drives Alterations in Mesangial Cells through Stabilization of N-Myc in Diabetic Nephropathy

Angiotensin II type 2 receptor gene polymorphisms and serum angiotensin-converting enzyme level in Egyptian children with systemic lupus erythematosus

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