Hydrogen sulfide inhibits the renal fibrosis of obstructive nephropathy

Abstract

Hydrogen sulfide has recently been found decreased in chronic kidney disease. Here we determined the effect and underlying mechanisms of hydrogen sulfide on a rat model of unilateral ureteral obstruction. Compared with normal rats, obstructive injury decreased the plasma hydrogen sulfide level. Cystathionine-β-synthase, a hydrogen sulfide-producing enzyme, was dramatically reduced in the ureteral obstructed kidney, but another enzyme cystathionine-γ-lyase was increased. A hydrogen sulfide donor (sodium hydrogen sulfide) inhibited renal fibrosis by attenuating the production of collagen, extracellular matrix, and the expression of α-smooth muscle actin. Meanwhile, the infiltration of macrophages and the expression of inflammatory cytokines including interleukin-1β, tumor necrosis factor-α, and monocyte chemoattractant protein-1 in the kidney were also decreased. In cultured kidney fibroblasts, a hydrogen sulfide donor inhibited the cell proliferation by reducing DNA synthesis and downregulating the expressions of proliferation-related proteins including proliferating cell nuclear antigen and c-Myc. Further, the hydrogen sulfide donor blocked the differentiation of quiescent renal fibroblasts to myofibroblasts by inhibiting the transforming growth factor-β1-Smad and mitogen-activated protein kinase signaling pathways. Thus, low doses of hydrogen sulfide or its releasing compounds may have therapeutic potentials in treating chronic kidney disease.

Tadalafil Integrates Nitric Oxide-Hydrogen Sulfide Signaling to Inhibit High Glucose-induced Matrix Protein Synthesis in Podocytes

“…Additionally, H 2 S is not beneficial in all models of renal injury as its effect can vary with the context (70). Whereas H 2 S ameliorates renin-induced hypertension (71), ischemia-reperfusion injury in the kidney and heart (17,20), obstructive kidney injury (72), preeclampsia (73), and hyperhomocysteinemia-induced chronic kidney disease (74) and protects endothelium against high glucose (75), it assumes a pathologic role as a mediator in cisplatinum-induced kidney cell injury (76), streptozotocin-induced pancreatic ␤ cell injury (77), and colon carcinoma (78). These considerations suggest that a critical evaluation of PDE5 inhibitors and H 2 S donors should be done in long term models of kidney injury in diabetes.…”

GYY4137, a Slow-Releasing Hydrogen Sulfide Donor, Ameliorates Renal Damage Associated with Chronic Obstructive Uropathy

“…Two recent studies have demonstrated that exogenous H 2 S, released via sodium hydrosulfide (NaHS), can ameliorate damage associated with short-term ureteral obstruction 9,10 .…”

Hydrogen Sulfide Alleviates Diabetic Nephropathy in a Streptozotocin-induced Diabetic Rat Model

“…H 2 S has also been found to exhibit antifibrotic effects in obstructed nephropathy and to inhibit the proliferation and differentiation of renal fibroblasts. The antifibrotic mechanisms of H 2 S may involve its anti-inflammation, as well as its blockade of TGF-␤1 and MAPK signaling (5). In this study, we established a streptozotocin-induced diabetic rat model to investigate whether H 2 S has protective effects against diabetic nephropathy.…”

“…Measurement of H 2 S Content-H 2 S levels were determined by the methylene blue method as described previously (5). The H 2 S concentration in plasma was expressed as micromoles/ liter, whereas the H 2 S content in kidney was expressed in nanomoles/mg of protein.…”