Deletion of Akt1 Promotes Kidney Fibrosis in a Murine Model of Unilateral Ureteral Obstruction.

Il Young Kim,Sang Soo Kim,Min Young Lee,Sang Heon Song,Sun Sik Bae,Eun Young Seong,Dong Won Lee,Soo Bong Lee,Mi Wha Park,Concetta Anna Dodaro

doi:10.1155/2020/6143542

Abstract

We investigated the role of Akt1, one of the three isoforms of Akt, in renal fibrosis using the murine model of unilateral ureteral obstruction (UUO). We subjected wild type and Akt1−/− mice to UUO. The Akt1 gene was silenced in vitro using short hairpin RNA delivered via a lentiviral vector in human proximal tubular cells (HK2 cells) and kidney fibroblasts (NRK-49F cells). The obstructive kidneys of Akt1−/− mice showed more severe tubulointerstitial fibrosis than those of wild type mice. The expression of fibronectin and type I collagen was significantly increased in obstructed kidneys of Akt1−/− mice compared to those of wild type mice. The important finding was that the expression of transforming growth factor β1 (TGFβ1) was significantly increased in the Akt1−/− mice compared to the wild type mice. The knockdown of Akt1 enhanced the expression of TGFβ1 in HK2 cells. Interestingly, the upregulation of TGFβ1 due to genetic knockdown of Akt1 was associated with activation of signal transducer and activator of transcript 3 (STAT3) independently of the Smad pathway in NRK-49F and HK2 cells. Immunohistochemical staining also showed that expression of phosphorylated STAT3 was more increased in Akt1−/− mice than in wild type mice after UUO. Additionally, the deletion of Akt1 led to apoptosis of the renal tubular cells in both in vivo and in vitro studies. Conclusively, these results suggest that the deletion of Akt1 may contribute to renal fibrosis via induction of the TGFβ1/STAT3 pathway in a murine model of UUO.

Highlights

Chronic kidney disease (CKD) is a highly prevalent disease, which is caused by multiple etiologies including diabetes mellitus (DM), hypertension, and glomerulonephritis
After ureteral obstruction (UUO) surgery, the obstructed kidneys in both wild type and Akt1−/− mice showed the typical features of obstructive nephropathy including tubular dilatation and renal tubulointerstitial fibrosis as evidenced by Masson’s trichrome staining
CKD is a syndromic disease characterized by diminished renal function, which microscopically manifests as glomerulosclerosis and tubulointerstitial fibrosis combined with tubular apoptosis

Summary

Introduction

Chronic kidney disease (CKD) is a highly prevalent disease, which is caused by multiple etiologies including diabetes mellitus (DM), hypertension, and glomerulonephritis. The prevalence of CKD varies between 7% and 12% in different regions of the world [1], and the Korean National Health and Nutritional Examination Survey (2011-2013) reported a prevalence of 8.2% in adults aged ≥20 years [2]. Renal fibrosis is a common characteristic of CKD and is referred to as “glomerulosclerosis” or “tubulointerstitial fibrosis” according to its anatomic location [3, 4]. These findings are usually accompanied by peritubular capillary rarefaction, interstitial inflammation, and tubular atrophy [3]. Tubular apoptosis can importantly contribute to renal fibrosis [5]

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