Cellular and Molecular Mechanisms of Chronic Kidney Disease with Diabetes Mellitus and Cardiovascular Diseases as Its Comorbidities

Abstract

Chronic kidney disease (CKD), diabetes mellitus (DM), and cardiovascular diseases (CVD) are complex disorders of partly unknown genesis and mostly known progression factors. CVD and DM are the risk factors of CKD and are strongly intertwined since DM can lead to both CKD and/or CVD, and CVD can lead to kidney disease. In recent years, our knowledge of CKD, DM, and CVD has been expanded and several important experimental, clinical, and epidemiological associations have been reported. The tight cellular and molecular interactions between the renal, diabetic, and cardiovascular systems in acute or chronic disease settings are becoming increasingly evident. However, the (patho-) physiological basis of the interactions of CKD, DM, and CVD with involvement of multiple endogenous and environmental factors is highly complex and our knowledge is still at its infancy. Not only single pathways and mediators of progression of these diseases have to be considered in these processes but also the mutual interactions of these factors are essential. The recent advances in proteomics and integrative analysis technologies have allowed rapid progress in analyzing complex disorders and clearly show the opportunity for new efficient and specific therapies. More than a dozen pathways have been identified so far, including hyperactivity of the renin–angiotensin (RAS)–aldosterone system, osmotic sodium retention, endothelial dysfunction, dyslipidemia, RAS/RAF/extracellular-signal-regulated kinase pathway, modification of the purinergic system, phosphatidylinositol 3-kinase (PI 3-kinase)-dependent signaling pathways, and inflammation, all leading to histomorphological alterations of the kidney and vessels of diabetic and non-diabetic patients. Since a better understanding of the common cellular and molecular mechanisms of these diseases may be a key to successful identification of new therapeutic targets, we review in this paper the current literature about cellular and molecular mechanisms of CKD.

Dietary NaCl affects bleomycin-induced lung fibrosis in mice

“…[8–11] The mechanisms by which elevated dietary NaCl promotes disease apart from elevated blood pressure are diverse, and appear to include endothelial cell damage, alterations in the sympathetic nervous system which regulates the cardiovascular and renal systems, and enhanced inflammatory responses. [7,10,12,13] High NaCl promotes inflammatory responses in vitro and in vivo by inhibiting anti-inflammatory regulatory T cells (Treg), promoting pro-inflammatory Th17 T cells, and enhancing production of inflammatory cytokines. [8,14–16] In addition, to help form fibrotic lesions, monocytes can differentiate into fibroblast-like cells called fibrocytes, and we observed that high concentrations of NaCl in tissue culture potentiate human fibrocyte differentiation, and reduce the ability of the endogenous fibrocyte differentiation inhibitor Serum Amyloid P to inhibit fibrocyte differentiation.…”

Tangshen formula improves inflammation in renal tissue of diabetic nephropathy through SIRT1/NF-κB pathway

“…Inflammation has a vital role in the development of DN. High levels of blood glucose and hemodynamic disorder may cause apoptosis and shedding of kidney cells, including podocytes and proximal tubular epithelial cells, leading to the activation of leukocyte, along with the increasing recruitment of inflammatory chemokine factors (22).…”

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“…Regarding the kidney, glycosides maintain the cellular transport of sodium and potassium in a variety of tissues, because many drugs are infused into one renal artery, resulting from inhibition of renal tubular function manifested by a profound natriuresis, chlorosis, and diuresis. Coumarins and saponins possess a fantastic anti-inflammatory with antioxidant properties, which plays a protective role during acute kidney injury 23,24 . The flavonoids reversed the increased expression of enzyme modulators and improved kidney function; while alkaloids protect rat's kidney cells against gentamicin-induced glomerulonephritis.…”