Regulation of cystathionine-beta-synthase (CBS) mediated hydrogen sulfide (H2S) production and its biological function

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Homocysteine (Hcy) and hydrogen sulfide (H2S) are two important molecules produced in the body during the metabolism of sulfur amino acids (i.e. methionine, cysteine). Hcy is an intermediate amino acid produced through the conversion of essential amino acid methionine to cysteine. Hcy can either be regenerated to methionine as well as metabolized to cysteine or H2S. Cystathionine beta-synthase (CBS) is a key enzyme that regulates Hcy metabolism and H2S generation. Reduced CBS enzyme activity leads to (1) increased Hcy and (2) decreased H2S levels in the blood. CBS enzyme is present in several organs including the kidney that plays a key role in regulating sulfur amino acid and Hcy metabolism. It has long been known that too much Hcy in the circulation, a condition called hyperhomocysteinemia, can cause multiple organ injury. Hyperhomocysteinemia is often found in persons with kidney failure. One of the common causes of kidney failure is ischemia-reperfusion injury. Ischemia is a hypoxic condition with decreased or no blood flow to the tissue and reperfusion is the restoration of blood flow to the ischemic tissue. The affected tissue undergoes oxidative stress, a condition in which cells are damaged by reactive oxygen species. Oxidative stress occurs when there is an imbalance between the production of reactive oxygen species and the detoxifying capability of antioxidant defense mechanisms. We have observed that ischemia-reperfusion causes a reduction of CBS enzyme activity leading to Hcy accumulation in the kidney. Hcy, in turn, stimulates the production of reactive oxygen species in the kidney causing oxidative stress and cell death. The H2S level in the kidney is severely decreased upon ischemia-reperfusion and is inversely associated with tissue damage. At physiological levels, H2S acts as a vasodilator and neurotransmitter. However, the biological function of H2S in the kidney is not well understood. In the proposed research, we aim to identify (1) the role that H2S plays in the kidney (2) whether regulation of H2S synthesis through restoration of CBS activity offers any protective effect against ischemia-reperfusion induced oxidative stress and kidney damage.