Podocyte-Specific Loss of Krüppel-Like Factor 6 Increases Mitochondrial Injury in Diabetic Kidney Disease

Horne, Sylvia J.; Vasquez, Jessica M; Guo, Yiqing; Ly, Victoria; Piret, Siân E.; Leonardo, Alexandra R.; Ling, Jason; Revelo, Mônica P.; Bogenhagen, Daniel F.; Yang, Vincent W.; He, John Cijiang; Mallipattu, Sandeep K.

doi:10.2337/db17-0958

Cited by 29 publications

(18 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In view of the important role of podocytes on DKD [31], we next examined the effect of MYDGF deficiency on podocytes.…”

Section: Mydgf Deficiency Promotes Podocyte Injury In Dkd Micementioning

confidence: 99%

MYDGF attenuates podocyte injury and proteinuria by activating Akt/BAD signal pathway in mice with diabetic kidney disease

Wang

et al. 2020

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis Myeloid-derived growth factor (MYDGF), mainly secreted by bone marrow-derived cells, has been known to promote glucagon-like peptide-1 production and improve glucose/lipid metabolism in mouse models of diabetes, but little is known about the functions of MYDGF in diabetic kidney disease (DKD). Here, we investigated whether MYDGF can prevent the progression of DKD. Methods In vivo experiments, both loss-and gain-of-function strategies were used to evaluate the effect of MYDGF on albuminuria and pathological glomerular lesions. We used streptozotocin-treated Mydgf knockout and wild-type mice on high fat diets to induce a model of DKD. Then, albuminuria, glomerular lesions and podocyte injury were evaluated in Mydgf knockout and wild-type DKD mice treated with adeno-associated virus-mediated Mydgf gene transfer. In vitro and ex vivo experiments, the expression of slit diaphragm protein nephrin and podocyte apoptosis were evaluated in conditionally immortalised mouse podocytes and isolated glomeruli from non-diabetic wild-type mice treated with recombinant MYDGF. Results MYDGF deficiency caused more severe podocyte injury in DKD mice, including the disruption of slit diaphragm proteins (nephrin and podocin) and an increase in desmin expression and podocyte apoptosis, and subsequently caused more severe glomerular injury and increased albuminuria by 39.6% compared with those of wild-type DKD mice (p < 0.01). Inversely, MYDGF replenishment attenuated podocyte and glomerular injury in both wild-type and Mydgf knockout DKD mice and then decreased albuminuria by 36.7% in wild-type DKD mice (p < 0.01) and 34.9% in Mydgf knockout DKD mice (p < 0.01). Moreover, recombinant MYDGF preserved nephrin expression and inhibited podocyte apoptosis in vitro and ex vivo. Mechanistically, the renoprotection of MYDGF was attributed to the activation of the Akt/Bcl-2-associated death promoter (BAD) pathway. Conclusions/interpretationThe study demonstrates that MYDGF protects podocytes from injury and prevents the progression of DKD, providing a novel strategy for the treatment of DKD.

show abstract

“…In view of the important role of podocytes on DKD [31], we next examined the effect of MYDGF deficiency on podocytes.…”

Section: Mydgf Deficiency Promotes Podocyte Injury In Dkd Micementioning

confidence: 99%

MYDGF attenuates podocyte injury and proteinuria by activating Akt/BAD signal pathway in mice with diabetic kidney disease

Wang

et al. 2020

Diabetologia

View full text Add to dashboard Cite

show abstract

“…Interactions between these two types of cells occur in areas rich in extracellular matrix (ECM) ( 241 – 245 ). There are several factors affecting the mutual effect between ECs and PCs in pathological state, including changes in advanced glycation end products, increased leukocyte adhesion and inflammatory cytokines ( 246 , 247 ).…”

Section: Research Hotspots Of the Endothelial Dysfunction Of Diabetic...mentioning

confidence: 99%

Mechanistic Pathogenesis of Endothelial Dysfunction in Diabetic Nephropathy and Retinopathy

Yang

Liu

2022

Front. Endocrinol.

View full text Add to dashboard Cite

Diabetic nephropathy (DN) and diabetic retinopathy (DR) are microvascular complications of diabetes. Microvascular endothelial cells are thought to be the major targets of hyperglycemic injury. In diabetic microvasculature, the intracellular hyperglycemia causes damages to the vascular endothelium, via multiple pathophysiological process consist of inflammation, endothelial cell crosstalk with podocytes/pericytes and exosomes. In addition, DN and DR diseases development are involved in several critical regulators including the cell adhesion molecules (CAMs), the vascular endothelial growth factor (VEGF) family and the Notch signal. The present review attempts to gain a deeper understanding of the pathogenesis complexities underlying the endothelial dysfunction in diabetes diabetic and retinopathy, contributing to the development of new mechanistic therapeutic strategies against diabetes-induced microvascular endothelial dysfunction.

show abstract

“…It was demonstrated that KLF6 modulated the mitochondrial functions by preventing the activation of the cytochrome C-mediated intrinsic apoptotic pathway [ 75 ]. A subsequent study revealed that KLF6 was also involved in protecting the mitochondria from injury and apoptosis under diabetic conditions [ 76 ]. In the central nervous system (CNS), KLF6 interacted with STAT3 to coregulate the expression of genes involved in axon and corticospinal tract neurons regeneration following injury [ 77 ].…”

Section: Klf6 Roles In Normal Physiological Processesmentioning

confidence: 99%

Two Sides of the Same Coin: The Roles of KLF6 in Physiology and Pathophysiology

et al. 2020

View full text Add to dashboard Cite

The Krüppel-like factors (KLFs) family of proteins control several key biological processes that include proliferation, differentiation, metabolism, apoptosis and inflammation. Dysregulation of KLF functions have been shown to disrupt cellular homeostasis and contribute to disease development. KLF6 is a relevant example; a range of functional and expression assays suggested that the dysregulation of KLF6 contributes to the onset of cancer, inflammation-associated diseases as well as cardiovascular diseases. KLF6 expression is either suppressed or elevated depending on the disease, and this is largely due to alternative splicing events producing KLF6 isoforms with specialised functions. Hence, the aim of this review is to discuss the known aspects of KLF6 biology that covers the gene and protein architecture, gene regulation, post-translational modifications and functions of KLF6 in health and diseases. We put special emphasis on the equivocal roles of its full-length and spliced variants. We also deliberate on the therapeutic strategies of KLF6 and its associated signalling pathways. Finally, we provide compelling basic and clinical questions to enhance the knowledge and research on elucidating the roles of KLF6 in physiological and pathophysiological processes.

show abstract

Podocyte-Specific Loss of Krüppel-Like Factor 6 Increases Mitochondrial Injury in Diabetic Kidney Disease

Cited by 29 publications

References 57 publications

MYDGF attenuates podocyte injury and proteinuria by activating Akt/BAD signal pathway in mice with diabetic kidney disease

MYDGF attenuates podocyte injury and proteinuria by activating Akt/BAD signal pathway in mice with diabetic kidney disease

Mechanistic Pathogenesis of Endothelial Dysfunction in Diabetic Nephropathy and Retinopathy

Two Sides of the Same Coin: The Roles of KLF6 in Physiology and Pathophysiology

Contact Info

Product

Resources

About