Diabetic Nephropathy and Gaseous Modulators

Abstract

Diabetic nephropathy (DN) remains the leading cause of vascular morbidity and mortality in diabetes patients. Despite the progress in understanding the diabetic disease process and advanced management of nephropathy, a number of patients still progress to end-stage renal disease (ESRD). The underlying mechanism still needs to be clarified. Gaseous signaling molecules, so-called gasotransmitters, such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S), have been shown to play an essential role in the development, progression, and ramification of DN depending on their availability and physiological actions. Although the studies on gasotransmitter regulations of DN are still emerging, the evidence revealed an aberrant level of gasotransmitters in patients with diabetes. In studies, different gasotransmitter donors have been implicated in ameliorating diabetic renal dysfunction. In this perspective, we summarized an overview of the recent advances in the physiological relevance of the gaseous molecules and their multifaceted interaction with other potential factors, such as extracellular matrix (ECM), in the severity modulation of DN. Moreover, the perspective of the present review highlights the possible therapeutic interventions of gasotransmitters in ameliorating this dreaded disease.

Keywords: carbon monoxide; diabetic nephropathy; hydrogen sulfide; nitric oxide.

Figure 1

Diabetic nephropathy and gaseous molecules. Schematic representations of the pathway of synthesis of the gasotransmitters and their beneficial effects in diabetic nephropathy: (A) H₂S is synthesized from L-cysteine by the enzymatic action of cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), as well as by the combined action of 3-mercaptopyruvate sulfurtransferase (3-MST) and cysteine aminotransferase (CAT). (B) NO is synthesized by the catalytic activity of nitric oxide synthase (NOS) via a series of redox reactions, with degradation of L-arginine to L-citrulline in the presence of NADPH. (C) In the presence of functional heme oxygenase (HO), the porphyrin ring of heme is broken and oxidized to produce CO, ferrous iron, and biliverdin. These gasotransmitters exert several responses, some of them mentioned in the figure, which help to prevent deleterious effects of DN.

Figure 2

Receptor-mediated DN and gaseous molecules. Schematic representations of the role of gaseous molecules in receptor-mediated DN. Elevated expression of NMDAR-1 induces pathophysiological changes leading to the DN, while H₂S treatment ameliorates such effects. Activation of NMDA-R stimulates neuronal NO synthase (nNOS) leading to the synthesis of NO, which mitigates pathophysiological changes in diabetic kidney and maintains normal renal functions. H₂S and CO can activate PPARγ, which helps in the alleviation of renovascular remodeling and confers renal protection. Together, renoprotection is also associated with the activation of PPARγ, simultaneous increase in NO production, and reduction in systemic blood pressure.

Figure 3

Matrix protein and gaseous molecules. Schematic representations of role of matrix proteins and their differential regulations by gaseous molecules in DN. During development of DN, deposition of the ECM proteins in the mesangium, renal tubulointerstitium of the glomerulus, and the glomerular basement membranes (GBMs) leads to renal fibrosis. Gasotransmitters, i.e., CO, NO, and H₂S, facilitate amelioration of the adverse effect of matrix remodeling through differential regulations of the matrix proteins during DN.