Mercapturate Pathway in the Tubulocentric Perspective of Diabetic Kidney Disease

Abstract

<b><i>Background:</i></b> The recent growing evidence that the proximal tubule underlies the early pathogenesis of diabetic kidney disease (DKD) is unveiling novel and promising perspectives. This pathophysiological concept links tubulointerstitial oxidative stress, inflammation, hypoxia, and fibrosis with the progression of DKD. In this new angle for DKD, the prevailing molecular mechanisms on proximal tubular cells emerge as an innovative opportunity for prevention and management of DKD as well as to improve diabetic dysmetabolism. <b><i>Summary:</i></b> The mercapturate pathway (MAP) is a classical metabolic detoxification route for xenobiotics that is emerging as an integrative circuitry detrimental to resolve tubular inflammation caused by endogenous electrophilic species. Herein we review why and how it might underlie DKD. <b><i>Key Messages:</i></b> MAP is a hallmark of proximal tubular cell function, and cysteine-<i>S</i>-conjugates might represent targets for early intervention in DKD. Moreover, the biomonitoring of urinary mercapturates from metabolic inflammation products might be relevant for the implementation of preventive/management strategies in DKD.

Diastolic dysfunction and impaired cardiac output reserve in dysmetabolic nonhuman primate with proteinuria

“…Proteinuria is an early sign and sensitive biomarker for diabetic nephropathy [36][37][38], which is strongly correlated with increased risk of cardiovascular and cerebrovascular diseases [33,39,40]. In patients with metabolic disorders and diabetes, the initial histopathology change is tubular injury that leads to protein leakage in early stages of diabetic nephropathy before the global glomerular ltration function is compromised [41,42]. Instead, hyperglycemia could even change kidney hemodynamics, leading to glomerular hyper ltration in early stages of diabetes which further contributes to the progression of kidney injury [43].…”

N-Acetylcysteine Serves as Substrate of 3-Mercaptopyruvate Sulfurtransferase and Stimulates Sulfide Metabolism in Colon Cancer Cells

“…It is important to note that, in addition to affording protection from oxidative stress, N -AceCysSSH may also increase the drug detoxifying capacity of cancer cells, thus promoting chemoresistance. Indeed, acetylation of cysteine-S-drug conjugates by microsomal NAT8 into the corresponding mercapturate is a crucial step for drug excretion in the urine [16,17]. On this basis, it is envisaged that conjugation of MST-derived N -AceCysSSH with an exogenous alkylating/oxidative drug will prompt the latter for its excretion.…”

“…Therefore, many of the biological effects attributed to H 2 S are currently believed to be mediated by sulfane sulfur species [10,11,12,13], whose antioxidant and cytoprotective action has been clearly established (reviewed e.g., in [14]). Moreover, sulfane sulfur species like persulfides have an increased affinity for exogenous toxins with respect to their thiol counterparts [15,16,17].…”

The mercapturomic profile of health and non-communicable diseases

“…LTE4 mercapturate formation is mediated by NAT8 activity as described by the team of Veiga da Cunha (2010) [3]. CysTL are well known for their role in the pathophysiology of asthma and increasing evidence links these metabolites with non-communicable chronic inflammatory conditions [33,34], namely cardiovascular, neurologic and kidney disease [35] and cancer [36,37]. Altogether, non-communicable diseases represent the most common cause of death and multi-morbidity in the modern world [38].…”

“…Moreover, smoking habits did not affect LTE4 levels in exhaled breath condensate and the use of CysLTs receptor antagonists during asthma exacerbation did not affect LTE4 levels in urine [40]. Cys- S -conjugates which are disulfides were increased in children with difficult-to-treat asthma [34] and associated with asthma severity, including poorer control of symptomatology, greater medication use and a worse response to glucocorticoid therapy [48].…”