Abstract
ABSTRACTRenal fibrosis is a common feature of renal failure resulting from multiple etiologies, including diabetic nephropathy, hypertension and inherited renal disorders. However, the mechanisms of renal fibrosis are incompletely understood and we therefore explored these by establishing a mouse model for a renal tubular disorder, referred to as autosomal dominant tubulointerstitial kidney disease (ADTKD) due to missense uromodulin (UMOD) mutations (ADTKD-UMOD). ADTKD-UMOD, which is associated with retention of mutant uromodulin in the endoplasmic reticulum (ER) of renal thick ascending limb cells, is characterized by hyperuricemia, interstitial fibrosis, inflammation and renal failure, and we used targeted homologous recombination to generate a knock-in mouse model with an ADTKD-causing missense cysteine to arginine uromodulin mutation (C125R). Heterozygous and homozygous mutant mice developed reduced uric acid excretion, renal fibrosis, immune cell infiltration and progressive renal failure, with decreased maturation and excretion of uromodulin, due to its retention in the ER. The ER stress marker 78 kDa glucose-regulated protein (GRP78) was elevated in cells expressing mutant uromodulin in heterozygous and homozygous mutant mice, and this was accompanied, both in vivo and ex vivo, by upregulation of two unfolded protein response pathways in primary thick ascending limb cells from homozygous mutant mice. However, this did not lead to an increase in apoptosis in vivo. Thus, we have developed a novel mouse model for renal fibrosis, which will be a valuable resource to decipher the mechanisms linking uromodulin mutations with ER stress and renal fibrosis.
Highlights
Renal fibrosis is an integral factor in progression to end-stage renal failure (ESRF), regardless of the primary etiology, which may include diabetic nephropathy, hypertension or monogenic disorders (Eddy, 2014)
We have generated a mouse model with an Autosomal dominant tubulointerstitial kidney disease (ADTKD) disease-causing UMOD mutation, that displays: defective uric acid excretion; urinary concentrating defects; renal failure; defective uromodulin trafficking, maturation and secretion; renal fibrosis; interstitial immune cell infiltration; and endoplasmic reticulum (ER) stress with upregulation of the unfolded protein response (UPR) in the thick ascending limb (TAL). This model is representative of ADTKD-UMOD patients, who develop hyperuricemia, low fractional excretion of uric acid (FEUA) and gout, chronic renal failure, tubulointerstitial nephropathy, glomerulosclerosis and lymphocytic infiltration (Lhotta et al, 1998; Turner et al, 2003). This mouse provides an in vivo model to study mechanisms of renal fibrosis and ER stress
In female Umod125R/125R mice, this decreased uric acid excretion was detected after the onset of renal failure, as measured by a significantly increased plasma urea, since 8-week-old Umod125R/125R females had an elevated plasma urea, but a similar uric acid excretion compared to Umod+/+ females
Summary
Renal fibrosis is an integral factor in progression to end-stage renal failure (ESRF), regardless of the primary etiology, which may include diabetic nephropathy, hypertension or monogenic disorders (Eddy, 2014). Autosomal dominant tubulointerstitial kidney disease (ADTKD), a monogenic cause of renal fibrosis, is characterized by urine concentrating defects, interstitial nephropathy with immune cell infiltration and glomerulosclerosis, and progressive loss of renal function leading to ESRF (Eckardt et al, 2015). In addition to the general clinical characteristics of ADTKD, patients with ADTKD-UMOD present with elevated serum urate concentrations due to low fractional excretion of uric acid (FEUA)
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