Telmisartan Ameliorates Nephropathy in Metabolic Syndrome by Reducing Leptin Release From Perirenal Adipose Tissue

Abstract

Abstract-Metabolic syndrome (MetS) is associated with nephropathy. Along with common risk factors such as hypertension and hyperglycemia, adipocytokines released from perirenal adipose tissue (PRAT) are implicated in the pathogenesis of MetS nephropathy. The study was designed to elucidate the adverse effects of PRAT-derived leptin on nephropathy and to determine whether the angiotensin II type 1 receptor antagonist telmisartan exerts a renoprotective effect by decreasing the PRAT-derived leptin level in the high-fat diet-induced MetS rat. In MetS rats, PRAT-derived leptin expression increased concomitant with dysfunction of adipogenesis, and the activities of the angiotensin II-angiotensin II type 1 receptor and the angiotensin-converting enzyme 2-angiotensin (1-7)-Mas receptor axes were imbalanced in PRAT. PRAT-derived leptin from MetS rats promoted proliferation of rat glomerular endothelial cells (GERs) by activating the p38 MAPK (mitogenactivated protein kinase) pathway, thereby contributing to the development of nephropathy. Long-term telmisartan treatment improved metabolic parameters and renal function, decreased the amount of PRAT, promoted adipogenesis, increased the expression of angiotensin-converting enzyme 2, restored balanced activities of the angiotensin II-AT1R and angiotensin-converting enzyme 2-angiotensin (1-7)-Mas axes, and exerted an indirect renoprotective effect on MetS rats by decreasing PRAT-derived leptin release. Our results demonstrate a novel link between nephropathy and PRAT in MetS and show that telmisartan confers an underlying protective effect on visceral adipose tissue and the kidney, suggesting that it has potential as a therapeutic agent for the treatment of MetS-associated nephropathy. (Hypertension. 2016;68:478-490.

Para‐perirenal distribution of body fat is associated with reduced glomerular filtration rate regardless of other indices of adiposity in hypertensive patients

“…First, PUFT secretes paracrine substances with functional or metabolic renal action that could play a key role in the development of nephropathy. In a previous study, Li et al found that perirenal adipose tissue exacerbated renal vascular remodeling in rats through the production of leptin, a well‐known adipocytokine with an adverse effect on kidney, and different paracrine substances were observed by other authors to have a similar action . In addition, excessive free fatty acids released from PUFT could escape into the kidney and lead to renal lipotoxicity by increasing intracellular fatty acids metabolites .…”

“…In a previous study, Li et al 32 found that perirenal adipose tissue exacerbated renal vascular remodeling in rats through the production of leptin, a well-known adipocytokine with an adverse effect on kidney, and different paracrine substances were observed by other authors to have a similar action. 27,32 In addition, excessive free fatty acids released from PUFT could escape into the kidney and lead to renal lipotoxicity by increasing intracellular fatty acids metabolites. 31,46,47 PUFT might also reflect renal function better than other indices of visceral fat due to the different venous drainage of perirenal adipose tissue: In fact, it drains into the caval system, whereas the venous circulation of the visceral fat around omentum (detected by RA) is part of the portal axis, and this might produce different systemic effects.…”

“…PUFT might relate to renal function not only due to its relationship with visceral adiposity: some data exist about a potential paracrine action of the PUFT on kidney, and a mechanical interference on the intrarenal vascular and interstitial compartment has been described together with perirenal fat expansion …”

“…PUFT might relate to renal function not only due to its relationship with visceral adiposity: some data exist about a potential paracrine action of the PUFT on kidney, 32 and a mechanical interference on the intrarenal vascular and interstitial compartment has been described together with perirenal fat expansion. 29,33 The aim of our study was to assess, in hypertensive patients regardless of their metabolic status, the relationship between glomerular filtration rate and PUFT in comparison with traditional anthropometric indices of adiposity or other direct measurement of abdominal fat content, 34 for which no local mechanical or paracrine action on the kidney has yet been demonstrated.…”

High fat diet confers vascular hyper-contractility against angiotensin II through upregulation of MLCK and CPI-17

“…Our result also demonstrated increased plasma Ang II level in HFD-fed mice. It has been reported that Ang II involves in HFD-induced hypertension through various pathways including leptin-related nephropathy [26], restoration of sympathetic over-reactivity [27], megalin-dependent uptake of angiotensinogen into adipocytes [28], vascular oxidative stress and endothelial dysfunction [29], and increased VSM reactivity [131430]. Increased VSM reactivity to Ang II in HFD-fed individuals is reported to be attributed to increased expression of AT1R and ACE 2 [13], and reactive oxygen species (ROS) overproduction and enhanced release of Ca 2+ induced by Ang II [14].…”