More VEGF, more life—and health span: Advanced aging is celebrated but its ill effects, deterioration at the cell, tissue, and organ levels, are not. Grunewald et al . provide evidence for the vascular theory of aging, which reports that age-related decrease of vascular function is a driver of organismal aging at large (see the Perspective by Augustin and Kipnis). Vascular endothelial growth factor (VEGF) signaling insufficiency underlies this vascular insufficiency in aged mice. A modest compensatory increase in circulatory VEGF was sufficient to preserve a young-like vascular homeostasis, alleviate multiple adverse age-related processes, and ameliorate a host of age-associated pathologies in mice. —BAP

Diabetic kidney disease (DKD) increases the risk for mortality and is the leading cause of end-stage renal disease. Treatment with sodium-glucose cotransporter 2 inhibitors (SGLT2i) attenuates the progression of DKD, especially in patients with advanced kidney disease. Herein, we show that in diabetes, mTORC1 activity is increased in renal proximal tubule cells (RPTCs) along with enhanced tubule-interstitial fibrosis; this is prevented by SGLT2i. Constitutive activation of mTORC1 in RPTCs induces renal fibrosis and failure and abolishes the renal-protective effects of SGLT2i in diabetes. On the contrary, partial inhibition of mTORC1 in RPTCs prevents fibrosis and the decline in renal function. Stimulation of mTORC1 in RPTCs turns on a pro-fibrotic program in the renal cortex, whereas its inhibition in diabetes reverses the alterations in gene expression. We suggest that RPTC mTORC1 is a critical node that mediates kidney dysfunction in diabetes and the protective effects of SGLT2i by regulating fibrogenesis.

Obesity-related structural and functional changes in the kidney develop early in the course of obesity and occur independently of hypertension, diabetes, and dyslipidemia. Activating the renal cannabinoid-1 receptor (CB₁R) induces nephropathy, whereas CB₁R blockade improves kidney function. Whether these effects are mediated via a specific cell type within the kidney remains unknown. Here, we show that specific deletion of CB₁R in the renal proximal tubule cells did not protect the mice from obesity, but markedly attenuated the obesity-induced lipid accumulation in the kidney and renal dysfunction, injury, inflammation, and fibrosis. These effects associated with increased activation of liver kinase B1 and the energy sensor AMP-activated protein kinase, as well as enhanced fatty acid β-oxidation. Collectively, these findings indicate that renal proximal tubule cell CB₁R contributes to the pathogenesis of obesity-induced renal lipotoxicity and nephropathy by regulating the liver kinase B1/AMP-activated protein kinase signaling pathway.

Altered glucose reabsorption via the facilitative glucose transporter 2 (GLUT2) during diabetes may lead to renal proximal tubule cell (RPTC) injury, inflammation, and interstitial fibrosis. These pathologies are also triggered by activating the cannabinoid-1 receptor (CB₁R), which contributes to the development of diabetic nephropathy (DN). However, the link between CB₁R and GLUT2 remains to be determined. Here, we show that chronic peripheral CB₁R blockade or genetically inactivating CB₁Rs in the RPTCs ameliorated diabetes-induced renal structural and functional changes, kidney inflammation, and tubulointerstitial fibrosis in mice. Inhibition of CB₁R also downregulated GLUT2 expression, affected the dynamic translocation of GLUT2 to the brush border membrane of RPTCs, and reduced glucose reabsorption. Thus, targeting peripheral CB₁R or inhibiting GLUT2 dynamics in RPTCs has the potential to treat and ameliorate DN. These findings may support the rationale for the clinical testing of peripherally restricted CB₁R antagonists or the development of novel renal-specific GLUT2 inhibitors against DN.

Background and Purpose: Obesity, an important risk factor for developing chronic kidney disease (CKD), affects the kidneys by two main molecular signalling pathways: the endocannabinoid/CB₁ receptor system, whose activation in obesity promotes renal inflammation, fibrosis, and injury, and the inducible NOS (iNOS), which generates ROS resulting in oxidative stress. Hence, a compound that inhibits both peripheral CB₁ receptors and iNOS may serve as an effective therapeutic agent against obesity‐induced CKD.Experimental Approach: Here, we describe the effect of a novel peripherally restricted, orally bioavailable dual CB₁ receptor/iNOS antagonist, MRI‐1867 (3 mg·kg⁻¹), in ameliorating obesity‐induced CKD, and compared its metabolic and renal efficacies to a stand‐alone peripheral CB₁ receptor antagonist (JD5037; 3 mg·kg⁻¹), iNOS antagonist (1400W; 10 mg·kg⁻¹), and pair feeding. Mice with high‐fat diet‐induced obesity were treated orally with these compounds or vehicle (Veh) for 28 days. Standard diet‐fed mice treated with Veh served as controls.Key Results: Enhanced expression of CB₁ receptors and iNOS in renal tubules was found in human kidney patients with obesity and other CKDs. The hybrid inhibitor ameliorated obesity‐induced kidney morphological and functional changes via decreasing kidney inflammation, fibrosis, oxidative stress, and renal injury. Some of these features were independent of the improved metabolic profile mediated via inhibition of CB₁ receptors. An additional interesting finding is that these beneficial effects on the kidney were partially associated with modulating renal adiponectin signalling.Conclusions and Implications: Collectively, our results highlight the therapeutic relevance of blocking CB₁ receptors and iNOS in ameliorating obesity‐induced CKD.