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Innate immunity in diabetic kidney disease

Nature Reviews Nephrology volume 16, pages 206–222 (2020)Cite this article

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Abstract

Increasing evidence suggests that renal inflammation contributes to the pathogenesis and progression of diabetic kidney disease (DKD) and that anti-inflammatory therapies might have renoprotective effects in DKD. Immune cells and resident renal cells that activate innate immunity have critical roles in triggering and sustaining inflammation in this setting. Evidence from clinical and experimental studies suggests that several innate immune pathways have potential roles in the pathogenesis and progression of DKD. Toll-like receptors detect endogenous danger-associated molecular patterns generated during diabetes and induce a sterile tubulointerstitial inflammatory response via the NF-κB signalling pathway. The NLRP3 inflammasome links sensing of metabolic stress in the diabetic kidney to activation of pro-inflammatory cascades via the induction of IL-1β and IL-18. The kallikrein–kinin system promotes inflammatory processes via the generation of bradykinins and the activation of bradykinin receptors, and activation of protease-activated receptors on kidney cells by coagulation enzymes contributes to renal inflammation and fibrosis in DKD. In addition, hyperglycaemia leads to protein glycation and activation of the complement cascade via recognition of glycated proteins by mannan-binding lectin and/or dysfunction of glycated complement regulatory proteins. Data from preclinical studies suggest that targeting these innate immune pathways could lead to novel therapies for DKD.

Key points

  • Renal inflammation involving the upregulation of inflammatory signalling pathways, release of cytokines and chemokines and infiltration of immune cells, contributes to the pathogenesis and progression of diabetic kidney disease (DKD).

  • In the diabetic kidney, recognition of endogenous danger-associated molecular patterns by Toll-like receptors (TLRs), particularly TLR2 and TLR4, induces inflammatory responses.

  • Inflammasome activation not only amplifies renal inflammation but also has a role in the development of fibrosis; pharmacological agents that target inflammasome components may have therapeutic potential in DKD.

  • The kallikrein–kinin system and protease-activated receptor signalling have been implicated in the progression of DKD; inhibition of kallikrein using kallistatin is renoprotective in diabetic mice.

  • The complement system is activated in human DKD; C5a and C3a receptor antagonists improve kidney fibrosis in rats with DKD, supporting a pathogenetic role of complement in this disease.

  • Targeting inflammatory signalling pathways is a promising novel therapeutic approach for DKD; further studies of the roles of innate immunity pathways in DKD may lead to the identification of novel drug targets.

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Fig. 1: The role of inflammation in the pathogenesis of diabetic kidney disease.
Fig. 2: Activation of TLR4 signalling in DKD.
Fig. 3: NLRP3 inflammasome activation in DKD.
Fig. 4: The roles of the KKS and PARs in DKD.
Fig. 5: Potential mechanisms of complement activation in diabetic kidney disease.

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Acknowledgements

The work of the authors is supported by the Research Grants Council (RGC, grant nos. C7018-16G, 17119818, 17151716), the Health and Medical Research Fund (HMRF, grant no. 05163596) of Hong Kong, the National Natural Science Fund (NSFC, grant no. 81870496) of China and by philanthropic donations from Winston Leung, K. K. Chan, Rita Liu (L & T Charitable Foundation Ltd.) and an Endowment Fund established at the University of Hong Kong for the Yu Professorship in Nephrology awarded to S.C.W.T.

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  1. Division of Nephrology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

    Sydney C. W. Tang & Wai Han Yiu

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Glossary

Sterile inflammation

Pathogen-free inflammation triggered by damage-associated molecular patterns that are released by cells in response to stress.

Homeostasis model assessment–insulin resistance

HOMA-IR. A method for evaluation of insulin sensitivity from basal (fasting) blood glucose and insulin levels.

Factor V Leiden (FVL) mutation

A genetic point mutation (R506Q) in the gene that encodes human coagulation factor V that results in resistance of factor V to inactivation by activated protein C and an increase in blood clotting. Carriers of the FVL mutation have an increased risk of venous thrombosis.

Lectins

Pattern recognition molecules that contain a C-type lectin domain (also known as a carbohydrate recognition domain).

Ingenuity Pathway Analysis

IPA. A web-based software application for analysis, integration and interpretation of data from high-throughput experiments such as next generation sequencing and microarray. IPA aids in the identification of key regulators and activities of biological systems.

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Tang, S.C.W., Yiu, W.H. Innate immunity in diabetic kidney disease. Nat Rev Nephrol 16, 206–222 (2020). https://doi.org/10.1038/s41581-019-0234-4

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