**1. Introduction**

Chronic kidney disease (CKD) is characterized by progressive loss of kidney function. The main risk factors of developing CKD are the combination of obesity, diabetes and hypertension, which is commonly referred to as metabolic syndrome. Other contributors are autoimmune diseases (e.g., glomerulonephritis), environmental exposures and genetic risk factors [1,2]. Morphologically, persistent low-grade renal inflammation and tubulointerstitial fibrosis are key hallmarks of CKD [3,4]. The complex interplay of fibroblasts, lymphocytes, tubular, and other cell types in the kidney lead to excessive extracellular matrix deposition and the further deterioration of renal function [5,6]. Although unspecific treatments strategies are available (e.g., medications lowering blood pressure), CKD progression is still poorly controlled.

In recent years, novel drug targets, such as transient receptor potential cation channel, subfamily C, and member 6 (TRPC6), emerged [7,8]. *TRPC6* mutations lead to glomerular injury and proteinuria, presumably involving the Ca2+ signaling pathway and resulting in progressive kidney failure [9–12]. Both TRPC6 gain-of-function and loss-of-function cause familial forms of focal segmental glomerulosclerosis (FSGS) [11,13]. Interestingly, in a murine model of kidney injury (unilateral ureteral obstruction (UUO)), *Trpc6*−/<sup>−</sup> deficiency and pharmacological blockade with BI-749327 ameliorated renal fibrosis in C57BL/6J mice [7,8]. Remarkably, these beneficial effects were not observed in the acute stage of kidney injury (AKI) [14]. Thus, TRPC6 inhibition may have effects on renal fibrogenesis during AKI-to-CKD transition. Given this state of affairs, TRPC6 inhibition seems to represent a promising new therapeutic approach to combat progressive renal failure since it potentially affects CKD at later stages after kidney injury. However, it is unknown whether TRPC6 inhibition is effective for inhibiting progressive tubulo-interstitial fibrosis in hypertension and metabolic syndrome.

Recently, by the chemical diversification of (+)-larixol originating from *Larix* decidua resin traditionally used for inhalation, its methylcarbamate congener, named SH045, was developed as a novel, highly potent, subtype-selective inhibitor of TRPC6 [15]. In the present study, we hypothesized that this novel selective TRPC6 inhibitor (SH045) [15] could ameliorate renal fibrogenesis in the New Zealand obese (NZO) mouse model, which is a polygenic model of metabolic syndrome [16]. We studied the therapeutic effects of the in vivo inhibition of TRPC6 by the novel blocker SH045 in the UUO mouse model of accelerated renal fibrogenesis utilizing these mice.
