Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes

Abstract

The protective role of Sirt1 in renal damage was investigated. Sirt1 in proximal tubules (PT) was downregulated before albuminuria occurred in streptozotocin-induced or obese-type (db/db) diabetic mice. PT-specific Sirt1 transgenic (TG) and knockout (KO) mice showed prevention and aggravation of the glomerular changes occurring in diabetes, respectively, and non-diabetic KO mice exhibited albuminuria, suggesting that Sirt1 in PT affects glomerular function. Downregulation of Sirt1 and upregulation of the tight junction protein Claudin-1 by Sirt1-mediated epigenetic regulation in podocytes contributed to albuminuria. These phenomena were not observed in 5/6 nephrectomized mice. We also demonstrated retrograde interplay from PT to glomeruli using nicotinamide mononucleotide (NMN) from conditioned medium, measurement of the auto-fluorescence of photoactivatable NMN, and injection of fluorescence-labeled NMN. In human subjects with diabetes, Sirt1 and Claudin-1 levels were correlated with proteinuria level. Sirt1 in PT protects against albuminuria in diabetes through maintaining NMN concentrations around glomeruli and controlling podocyte function.

Severity and Frequency of Proximal Tubule Injury Determines Renal Prognosis

“…Third, the crosstalk between tubules and the glomerulus could be postulated. 38,39 Glomerulosclerosis secondary to proximal tubule injuries is also observed in clinical situations. Mesoamerican nephropathy 40 represents interstitial fibrosis and glomerulosclerosis after repeated episodes of AKI.…”

Calorie restriction and sirtuins revisited

“…The secreted NMN then activates SIRT1 in a different kidney compartment, consisting of podocytes, to trigger stress resistance. The net effect of this circuit is the protection of the kidney and suppression of diabetic albuminuria (Hasegawa et al 2013).…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Progression from initial glomerular injury to glomerulosclerosis is mediated directly by injured cells and via an intensive crosstalk between glomerular cells (90)(91)(92)(93)(94)(95)(96) or even between tubular and glomerular cells (97).…”

“…TEC injury can also lead to upstream glomerular damage and glomerulosclerosis, suggesting that an intense cross-talk exists between virtually all renal cells (97,156). Systemic approaches identified novel players in renal fibrosis (157), such as the homeodomain interacting protein kinase 2 (HIPK2) in HIV transgenic mice (158).…”