Bone morphogenetic protein-7 delays podocyte injury due to high glucose

Petris, Laura De; Hruska, Keith A.; Chiechio, Santina; Liapis, Helen

doi:10.1093/ndt/gfm503

Cited by 55 publications

(54 citation statements)

References 40 publications

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“…In addition to the inhibitory effect on MMP expression, BMP-7 possibly inhibits the progression of glomerular pathogenesis in Col4a3 -/-mice at multiple steps. BMP-7 reduces the damage in podocytes (20,41,42) and mesangial cells (43)(44)(45) and attenuates the expression of inflammatory cytokines (46) and apoptosis in several types of cells (12,41). Antagonizing the beneficial effects of BMP-7 by USAG-1 might enhance these injuries and accelerate glomerular pathogenesis in Alport syndrome.…”

Section: Discussionmentioning

confidence: 99%

Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome

Tanaka¹,

Asada²,

Higashi³

et al. 2010

J. Clin. Invest.

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The glomerular basement membrane (GBM) is a key component of the filtering unit in the kidney. Mutations involving any of the collagen IV genes (COL4A3, COL4A4, and COL4A5) affect GBM assembly and cause Alport syndrome, a progressive hereditary kidney disease with no definitive therapy. Previously, we have demonstrated that the bone morphogenetic protein (BMP) antagonist uterine sensitization-associated gene-1 (USAG-1) negatively regulates the renoprotective action of BMP-7 in a mouse model of tubular injury during acute renal failure. Here, we investigated the role of USAG-1 in renal function in Col4a3 -/-mice, which model Alport syndrome. Ablation of Usag1 in Col4a3 -/-mice led to substantial attenuation of disease progression, normalization of GBM ultrastructure, preservation of renal function, and extension of life span. Immunohistochemical analysis revealed that USAG-1 and BMP-7 colocalized in the macula densa in the distal tubules, lying in direct contact with glomerular mesangial cells. Furthermore, in cultured mesangial cells, BMP-7 attenuated and USAG-1 enhanced the expression of MMP-12, a protease that may contribute to GBM degradation. These data suggest that the pathogenetic role of USAG-1 in Col4a3 -/-mice might involve crosstalk between kidney tubules and the glomerulus and that inhibition of USAG-1 may be a promising therapeutic approach for the treatment of Alport syndrome.

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Section: Discussionmentioning

confidence: 99%

Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome

Tanaka¹,

Asada²,

Higashi³

et al. 2010

J. Clin. Invest.

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“…In streptozotocin-induced diabetic rats, renal expression of BMP-7 was decreased by more than 90%, and this was accompanied by downregulation of the BMP type II receptor and the type I receptor ALK2 (44). Decrease of BMP-7 expression was also evidenced in mouse podocytes cultured under high glucose, and in renal biopsies of patients with diabetic nephropathy (45,46). Thus far, the latter study is the only report available demonstrating decrease of BMP-7 expression in human patients.…”

Section: Bmp-7 Expression In Renal Fibrosismentioning

confidence: 99%

“…Other protective effects of BMP-7 in proximal tubular epithelial cells include inhibition of TGF-β1 production, decrease of proinflammatory genes and chemoattractants, and inhibition of EMT induced by multiple myeloma light chains (36,50,51). Also in mesangial cells and podocytes, BMP-7 was able to inhibit adverse effects caused by TGFβ1, aldosterone, or high glucose (45,46,52,53). The remarkable potential of BMP-7 even to reverse fibrosis was demonstrated by its ability to induce formation of epithelial cell aggregates in cultures of adult renal fibroblasts, which was accompanied by acquisition of E-cadherin expression and decreased motility, indicating that true mesenchymal-to-epithelial transition (MET) might also be achieved (54).…”

Section: In Vitro Antifibrotic Effects Of Bmp-7 In Renal Cellsmentioning

confidence: 99%

Bone Morphogenetic Protein-7 and Connective Tissue Growth Factor: Novel Targets for Treatment of Renal Fibrosis?

Nguyen

Goldschmeding

2008

Pharm Res

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“…Podocytes are located on the outer level of the glomerular basement membrane and cover it with their foot processes [8][9][10] , and podocyte dysfunctions are involved in the development of renal damage in various renal disease model rats, such as hypertensive nephropathy, diabetic nephropathy, and nephrotic syndrome [11][12][13] . In in vitro investigations, high glucose loading on cultured podocytes was shown to enhance apoptosis, decrease the mRNA levels of podocyte-related factors, such as synaptopodin and podocin, and downregulate the expression of bone morphogenetic protein (BMP)-7 [14,15] .…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies demonstrated that BMP-7, a BMP subtype, was expressed in podocytes and renal tubular epithelial cells, and exhibited anti-fibrotic and renopro-tective effects in kidney [14,[18][19][20] . Morrissey et al [21] showed that the administration of BMP-7 to unilateral ureteral ligation model rats improved the glomerular filtration rate (GFR) and inhibited renal fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Pitavastatin Exhibits Protective Effects on Podocytes Accompanied by BMP-7 Up-Regulation and Rho Suppression

Ohigashi

Imai²,

Toba³

et al. 2016

Pharmacology

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Background/Aims: Podocytes injury is involved in the development of diabetic nephropathy. This study was designed to confirm the reno- and podocyte-protective effects of pitavastatin in diabetic rats and clarify its mechanisms. Methods: Wistar rats were divided into 4 treatment groups: control, streptozotocin (STZ; 55 mg/kg)-induced diabetes, STZ with pitavastatin (10 mg/kg/day), and STZ with tempol (1 mmol/l). Results: STZ-induced diabetic rats exhibited increases in urinary protein excretion and plasma creatinine, and a decrease in creatinine clearance. Pitavastatin significantly improved these parameters without reducing cholesterol levels, whereas tempol did not. The treatment with STZ-enhanced renal fibrosis, mesangial proliferation, transforming growth factor (TGF)-β, MCP-1 and suppressed Rho in association with decrement of bone morphogenetic protein (BMP)-7 expression in renal cortex. Moreover, STZ decreased podocyte related factors, podocin and nephrin, and BMP-7 in podocytes. Pitavastatin significantly ameliorated all these indices. On the other hand, improvement by tempol was found only in TGF-β, MCP-1 and histological changes. Conclusion: Pitavastatin exhibited reno- and podocyte-protective effects accompanied by BMP-7 preservation and Rho suppression.

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Bone morphogenetic protein-7 delays podocyte injury due to high glucose

Abstract: BMP-7 may confer resistance to hyperglycaemic injury via synaptopodin and podocin suggesting novel BMP7 therapies for diabetic glomerulosclerosis.

Cited by 55 publications

References 40 publications

Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome

Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome

Bone Morphogenetic Protein-7 and Connective Tissue Growth Factor: Novel Targets for Treatment of Renal Fibrosis?

Pitavastatin Exhibits Protective Effects on Podocytes Accompanied by BMP-7 Up-Regulation and Rho Suppression

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