Tubuloglomerular Communication in Diabetic Nephropathy

Abstract

Diabetic nephropathy (DN) is the leading cause for end-stage renal disease, whose main pathological changes were traditionally believed to reside in the glomerulus, although tubulointerstitial and vascular lesions are also well documented. This chapter focuses on the metabolic abnormalities of proximal tubules in the pathogenesis of DN since diabetes is a metabolic as well as a vascular disease, partly resulting from glucose toxicity. Sirt1 is an isoform of sirtuin, a NAD⁺-dependent deacetylase, and is a key molecule in glucose, lipid, and energy metabolism. Sirt1 has a protective role against diabetic renal damage through anti-oxidative, anti-inflammatory, and anti-apoptotic mechanisms in affected cells including mesangial cells, podocytes, and tubular cells under diabetic conditions. In diabetes, Sirt1 in the proximal tubule is downregulated before the onset of albuminuria. This downregulation is believed to disrupt the metabolism of NAD⁺, diminishing the replenishment of the glomerulus with nicotinamide mononucleotide (NMN) from the proximal tubule; this results in Sirt1 downregulation and tight junction protein claudin-1 upregulation in glomerular podocytes. Intracellular nicotinamide phosphoribosyltransferase (iNAMPT) regulation may be an important new therapeutic target for diabetic nephropathy. This tubuloglomerular communication forms a novel target for the treatment of DN. The typical example is the inhibition of SGLT2 in proximal tubules, which inhibits glomerular hyperfiltration and subsequent glomerular damage. The significance of these effects is clinically demonstrated in large trials such as the EMPA-REG OUTCOME study using empagliflozin and the CANVAS Program using canagliflozin. The regulation of proximal tubular cell function is becoming an increasingly important therapeutic strategy for DN.