Hydrogen Sulfide in Pharmacotherapy of Diabetic Kidney Disease

Diabetic kidney disease (DKD) is currently the leading cause of end-stage renal disease. It accounts for 40% of morbidity and mortality among the diabetic population despite optimal management. Its clinical hallmark includes persistent hyperglycemia, hypercreatininemia, uremia, sustained albuminuria, renal hemodynamic changes and elevated blood pressure. Histologically, DKD presents with excessive accumulation and deposition of extracellular matrix, leading to expansion of mesangial matrix, thickening of glomerular basement membrane and tubulointerstitial fibrosis. At the molecular level, accumulating evidence suggests that hyperglycemia or high glucose mediates renal injury in DKD via multiple molecular mechanisms such as induction of oxidative stress, upregulation of renal transforming growth factor beta-1 expression, production of pro-inflammatory cytokines, activation of fibroblasts and renin-angiotensin-aldosterone system, and depletion of adenosine triphosphate. Moreover, existing therapies only retard the disease progression but do not prevent or reverse it. Therefore, novel modes of pharmacotherapeutic intervention are in demand to target additional disease mechanisms. A substantial body of experimental evidence demonstrates that hydrogen sulfide (H2S), a gas with a historic notorious label, has recently been established to possess important therapeutic properties that prevent and/or reverses DKD development and progression of DKD by targeting several important molecular pathways, and therefore could be considered a novel pharmacological agent for DKD treatment. The aim of this chapter is to discuss recent experimental findings on the molecular mechanisms underlying the pharmacotherapeutic effects of H2S against DKD development and progression, and its translation from bench to bedside, which could lay the foundation for its future clinical use.