Exploring novel pathways and potential therapeutic targets for diabetic nephropathy: The interplay of podocytes and proximal tubular epithelial cells

Abstract

This article discusses a recent article by Zha et al, which explores new pathogenic pathways contributing to diabetic nephropathy in a study conducted on male mice. Diabetic kidney disease outcomes remain suboptimal; it is the leading cause of end-stage kidney disease in the developed world. Previous knowledge about diabetic nephropathy focused on glomerular pathology. Advancing knowledge led to the introduction of new pathogenic concepts beyond glomerulopathy. This work by Zha et al explored an important podocyte pathway and its link to the proximal tubular cells. Podocytes are essential for maintaining glomerular health and preserving body proteins. In a state of hyperglycaemic stress, podocytes show features of internalisation of nephrin, an integral surface protein of the podocytes. The novel pathway uncovered in this experimental study involved crosstalk between the podocytes and the proximal tubular cells, more precisely, the secretion of interleukin 6 (IL-6) and Rab5 by the proximal tubular cells. When the podocytes were cultured in the conditioned medium, this resulted in podocyte dysfunction. IL-6 neutralising antibodies ameliorated this effect. Nicotinamide mononucleotide is essential for the integrity of the proximal tubular cells. Interestingly, it has been found that nicotinamide mononucleotide treatment can disrupt the IL-6-Rab signalling between the proximal tubules and podocytes, leading to improved podocyte morphology and function. The clinical applicability of this novel pathway is yet to be explored; however, it is one of the key pathways mediating inflammation and dysfunction in diabetic nephropathy.

Keywords: Diabetic nephropathy; Diabetic kidney disease; Nicotinamide mononucleotide; Podocyte; Proximal tubular epithelial cells

Core Tip: This article sheds light on the interesting study by Zha et al. In this experimental study, a novel pathogenic pathway has been described. A novel concept was also demonstrated, namely the crosstalk between the podocytes and the proximal tubular epithelial cells. The crosstalk involves the secretion of interleukin 6 by the proximal tubular epithelial cells, which aggravates nephrin endocytosis in the podocytes using the Rab5 activation pathway. The application of nicotinamide mononucleotide nicotinamide mononucleotide intercepted the pathway. A new horizon for therapeutics could be further explored using the nicotinamide mononucleotide.