Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis

Abstract

Chronic kidney disease (CKD) remains one of the leading causes of death in the developed world and acute kidney injury (AKI) is now recognized as a major risk factor in its development. Understanding the factors leading to CKD after acute injury are limited by current animal models of AKI which concurrently target various kidney cell types such as epithelial, endothelial and inflammatory cells. Here we developed a mouse model of kidney injury using the Six2-Cre-LoxP technology to selectively activate expression of the simian diphtheria toxin receptor in renal epithelia derived from the metanephric mesenchyme. By adjusting the timing and dose of diphtheria toxin a highly selective model of tubular injury was created to define the acute and chronic consequences of isolated epithelial injury. The diphtheria toxin-induced sublethal tubular epithelial injury was confined to the S1 and S2 segments of the proximal tubule rather than being widespread in the metanephric mesenchyme derived epithelial lineage. Acute injury was promptly followed by inflammatory cell infiltration and robust tubular cell proliferation leading to complete recovery after a single toxin insult. In striking contrast, three insults to renal epithelial cells at one week intervals resulted in maladaptive repair with interstitial capillary loss, fibrosis and glomerulosclerosis which was highly correlated with the degree of interstitial fibrosis. Thus, selective epithelial injury can drive the formation of interstitial fibrosis, capillary rarefaction and potentially glomerulosclerosis, substantiating a direct role for damaged tubule epithelium in the pathogenesis of CKD.

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…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).…”

Hyperbaric oxygen therapy (HBOT) suppresses biomarkers of cell stress and kidney injury in diabetic mice

“…Urinary neutrophil gelatinase-associated lipocalin (NGAL), clusterin, and cystatin-C assays were performed on 22-h urine collections and reported as a ratio of biomarker to urine creatinine concentration using a microbead-based assay as described previously in Dr. Sabbisetti's laboratory at Brigham & Women's Hospital (Grgic et al 2012). Urine samples were incubated with microbeads coupled with NGAL, clusterin, cystatin-C antibodies, and recombinant standard proteins (R&D systems) for 1 h, washed three times with PBST (10 mM Na 2 HPO 4 , 137 mM NaCl, 1.8 mM KH 2 PO 4 , 2.7 mM KCl, 0.05 % Tween 20, pH 7.4), and incubated with detection antibody (R&D Systems), and the amount of analytes in the urine was determined using Bio-Plex 200.…”

NLRP3 regulates a non-canonical platform for caspase-8 activation during epithelial cell apoptosis

“…In the kidney, tubular epithelial cell apoptosis is a major component of disease that contributes to tubular atrophy and tubulointerstitial fibrosis. 18 The intestinal epithelium lies at the hostmicrobial interface and is key to maintaining gut homeostasis as well as directing the host response to the gut microbiota and to pathogenic microbes. Inflammasome genes such as NLRP3 and ASC are expressed in both gut and kidney epithelia.…”