Downregulation of the kidney glucagon receptor, essential for renal function and systemic homeostasis, contributes to chronic kidney disease
Open accessAbstract
The glucagon receptor (GCGR) in the kidney is expressed in nephron tubules. In humans and animal models with chronic kidney disease, renal GCGR expression is reduced. However, the role of kidney GCGR in normal renal function and in disease development has not been addressed. Here, we examined its role by analyzing mice with constitutive or conditional kidney-specific loss of the Gcgr. Adult renal Gcgr knockout mice exhibit metabolic dysregulation and a functional impairment of the kidneys. These mice exhibit hyperaminoacidemia associated with reduced kidney glucose output, oxidative stress, enhanced inflammasome activity, and excess lipid accumulation in the kidney. Upon a lipid challenge, they display maladaptive responses with acute hypertriglyceridemia and chronic proinflammatory and profibrotic activation. In aged mice, kidney Gcgr ablation elicits widespread renal deposition of collagen and fibronectin, indicative of fibrosis. Taken together, our findings demonstrate an essential role of the renal GCGR in normal kidney metabolic and homeostatic functions. Importantly, mice deficient for kidney Gcgr recapitulate some of the key pathophysiological features of chronic kidney disease.
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Activating kidney-specific glucagon receptors through the administration of a GIP/GLP-1/glucagon agonist may reverse hypertension and inflammation in the kidney that then ameliorates albuminuria.
“Activating kidney-specific glucagon receptors through the administration of a GIP/GLP-1/glucagon agonist may reverse hypertension and inflammation in the kidney that then ameliorates albuminuria.”
From The Effect of Retatrutide on Kidney Parameters in Participants With Type 2 Diabetes Mellitus and/or Obesity (2025) · cites this paper as [16]
The kidney-specific Gcgr-null mouse results report hypertension, renal inflammation, and albuminuria, and the discussion suggests that therapies targeting related renal signaling pathways could benefit kidney function (sections “Kidney-specific Gcgr-null mice display hypertension and kidney injury at baseline” and “Kidney-specific Gcgr KO mice exhibit CKD-associated renal homeostatic dysfunction”; page numbers unavailable). The paper does not show that administering a GIP/GLP-1/glucagon agonist activates kidney-specific receptors or reverses hypertension and inflammation, nor that those changes then ameliorate albuminuria. (LLM, conf=0.84)
Experimental — accuracy not yet measuredTargeting the glucagon receptor may exert direct kidney protective effects.
“Based on emerging data suggesting that targeting the glucagon receptor may exert direct kidney protective effects,16”
From The Effect of Retatrutide on Kidney Parameters in Participants With Type 2 Diabetes Mellitus and/or Obesity (2025) · cites this paper as [16]
In a mouse model, kidney-selective glucagon receptor deficiency led to hypertension and profound metabolic defects in the kidney including inflammation and fibrosis.
“In a mouse model, kidney-selective glucagon receptor deficiency led to hypertension and profound metabolic defects in the kidney including inflammation and fibrosis.16”
From The Effect of Retatrutide on Kidney Parameters in Participants With Type 2 Diabetes Mellitus and/or Obesity (2025) · cites this paper as [16]
Mice with kidney-specific glucagon receptor knockout have major kidney abnormalities including enhanced oxidative stress, enhanced activity of the inflammasome, and fibrosis, all features of CKD.
“These mice have major kidney abnormalities including enhanced oxidative stress, enhanced activity of the inflammasome, and fibrosis, all features of CKD.”
From GLP-1 agonists in the treatment of chronic kidney disease in type 2 diabetes and obesity (2025) · cites this paper as [80]
In older mice, blocking or genetically removing GIPR reduces lipid buildup in muscle.
“pharmacological or genetic inhibition of the GIPR has been shown to alleviate intramuscular lipid accumulation in aged mice108.”
From Transforming obesity: The advancement of multi-receptor drugs (2024) · cites this paper as [108]
The paper’s section on kidney-specific Gcgr-null mice reports increased lipid deposition in the kidney, not reduced lipid accumulation in muscle. The methods describe mice generally aged 3–5 months. Searches for GIPR inhibition and intramuscular lipid accumulation in aged mice found no passage addressing the claim; the indexed passages provide no page numbers. (LLM, conf=0.77)
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References 153 · Cited by 52
- Authors
- Wang, M.-Y., Zhang, Z., Zhao, S., Onodera, T., Sun, X.-N., Zhu, Q., Li, C., Li, N., Chen, S., Paredes, M., Gautron, L., Charron, M. J., Marciano, D. K., Gordillo, R., Drucker, D. J., & Scherer, P. E.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- The University of Texas at San Antonio Health Science Center (US)
- Albert Einstein College of Medicine (US)
- Mount Sinai Hospital (CA)
- Corresponding author
- Scherer, Philipp E.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2024-03
- Volume
- 36
- Issue
- 3
- Pages
- 575-597.e7
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC10932880
- OpenAlex
- W4390942364
- Cited by
- 52
- References
- 153
- Citations by year
- 2026: 22 · 2025: 17 · 2024: 13
- FWCI
- 14.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 369 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Toronto Banting and Best Diabetes Centre
- National Institutes of Health
- NIA (R00-AG068239)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK131537, R01-DK099110, R01-DK127274, R01-DK55758, RC2-DK118620)
- American Heart Association (855170)
- Max and Minnie Tomerlin Voelcker Fund
- Canadian Institutes of Health Research (154321)
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Keywords
- glucagon receptor, chronic kidney disease, renal tubules, hyperaminoacidemia, oxidative stress, inflammasome, lipid accumulation, hypertriglyceridemia, renal fibrosis, collagen deposition, fibronectin, renal metabolism, systemic homeostasis
- MeSH terms
- Animals, Homeostasis, Humans, Kidney, Lipids, Down-Regulation, Receptors, Glucagon, Mice, Knockout, Mice, Renal Insufficiency, Chronic
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