Hydrogen sulfide deficiency and diabetic renal remodeling: role of matrix metalloproteinase-9

Abstract

Kundu S, Pushpakumar SB, Tyagi A, Coley D, Sen U. Hydrogen sulfide deficiency and diabetic renal remodeling: role of matrix metalloproteinase-9. Am J Physiol Endocrinol Metab 304: E1365-E1378, 2013. First published April 30, 2013 doi:10.1152/ajpendo.00604.2012.-Matrix metalloproteinase-9 (MMP-9) causes adverse remodeling, whereas hydrogen sulfide (H2S) rescues organs in vascular diseases. The involvement of MMP-9 and H2S in diabetic renovascular remodeling is, however, not well characterized. We determined whether MMP-9 regulates H2S generation and whether H2S modulates con-Ϫ/Ϫ mice and in vitro cell culture were used in our study. Hyperglycemic Akita mice exhibited increased level of MMP-9 and decreased production of H2S. H2S-synthesizing enzymes cystathionine-␤-synthase and cystathionine-␥-lyase were also diminished. In addition, increased expressions of NMDA-R1 and connexin-40 and -43 were observed in diabetic kidney. As expected, MMP-9 mRNA was not detected in M9KO kidneys. However, very thin protein expression and activity were detected. No other changes were noticed in M9KO kidney. In DKO mice, all the above molecules showed a trend toward baseline despite hyperglycemia. In vitro, glomerular endothelial cells treated with high glucose showed induction of MMP-9, attenuated H2S production, NMDA-R1 induction, and dysregulated conexin-40 and -43 expressions. Silencing MMP-9 by siRNA or inhibition of NMDA-R1 by MK801 or H2S treatment preserved connexin-40 and -43. We conclude that in diabetic renovascular remodeling MMP-9 plays a major role and that H2S has therapeutic potential to prevent adverse diabetic renal remodeling.

Hydrogen sulfide in renal physiology, disease and transplantation – The smell of renal protection

“…This study showed upregulation of MMP-9 and downregulation of both CBS and CSE in renal tissue of diabetic (Akita, Ins2 Akita ) mice, whereas none of these changes occurred in double knockouts (Akita/MMP-9 −/− ). The relative H2S deficiency resulting from downregulation of its producing enzymes in turn is thought to upregulate N-methyl-d-aspartate receptor 1 and connexins 40 and 43 and thereby contribute to the adverse renal remodeling seen in diabetes [88]. In accordance, NaHS treatment has been reported to oppose the process of adverse renal remodeling in mice by adenosine monophosphate-activated protein kinase-dependent stimulation of autophagy and matrix metabolism [89].…”

Gasotransmitters in Vascular Complications of Diabetes

“…Akita mice (82). In nonobese diabetic mice, another mouse model of type 1 diabetes, it was also shown that diabetic mice had lower H 2 S levels compared with nondiabetic mice (83).…”

“…Renal protection via blood pressure reduction is also shown in angiotensin II-induced hypertension and proteinuria in rats (109). Other studies also suggest that H 2 S is a key modulator in renal remodeling and that its actions can be affected by the matrix metalloproteinase 9, which is shown to modulate CBS and CSE (82). In STZ-induced type 1 diabetic mice, the administration of H 2 S attenuated oxidative stress and inflammation, reduced mesangial cell proliferation, and inhibited the renin-angiotensin-aldosterone system (110).…”

Hydrogen Sulfide in Renal Physiology and Disease

“…MMP-9 expression and activity are increased in the renal parenchyma in Akita mice with type 1 diabetes due to oxidative stress. Using MMP9 knockout mice in their studies, Kundu et al have shown that MMP-9 is involved in the reduced renal expression of CBS and CSE, leading to a decrease in H2S generation in diabetic mice (47). These investigators have proposed a link between MMP-9 activation, reduced H2S generation, and activation of N-methyl-d-aspartate receptor, leading to abnormal regulation of the gap junction proteins, connexins, that may be involved in renovascular remodeling (47).…”

“…Using MMP9 knockout mice in their studies, Kundu et al have shown that MMP-9 is involved in the reduced renal expression of CBS and CSE, leading to a decrease in H2S generation in diabetic mice (47). These investigators have proposed a link between MMP-9 activation, reduced H2S generation, and activation of N-methyl-d-aspartate receptor, leading to abnormal regulation of the gap junction proteins, connexins, that may be involved in renovascular remodeling (47). H2S inhibits diabetes-induced kidney injury by several other mechanisms, including inhibition of signaling mechanisms that govern protein synthesis.…”