Diabetic Nephropathy and Proximal Tubular Damage

doi:10.1053/j.jrn.2014.10.020

Journal of Renal Nutrition

Volume 25, Issue 2, March 2015, Pages 230-233

https://doi.org/10.1053/j.jrn.2014.10.020 Get rights and content

Diabetic nephropathy (DN) is a major cause of uremia in developed societies. Inflammation is emerging as an important mechanism for its pathogenesis and progression. Herein, we review 4 recently described cellular receptors that have been shown to mediate diabetic interstitial kidney disease. Peroxisome proliferator-activated receptor-γ attenuates STAT-1 activation and has shown promise in renoprotection. Its clinical utility is limited mainly by fluid retention through upregulation of sodium–hydrogen exchanger-3 and aquaporin-1 channels in the proximal tubule. The bradykinin receptor 2 of the kallikrein–kinin system has been shown to mediate diabetic kidney injury and its blockade conferred renoprotective effects in animal models of DN. The related protease-activated receptor, especially receptor 4, has recently been shown to participate in DN. Further studies are required to confirm its role. Finally, the toll-like receptor, especially TLR4 and TLR2, has been verified in multiple models to be a significant sensor of and reactor to hyperglycemia and other diabetic substrates that orchestrate interstitial inflammation in DN.

Section snippets

The Peroxisome Proliferator-Activated Receptor

Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated nuclear hormone receptors belonging to the steroid receptor superfamily. The antidiabetic thiazolidinedione group of drugs, such as troglitazone and rosiglitazone, are specific synthetic ligands of PPAR-γ, and this interaction is responsible for the insulin-sensitizing and hypoglycemic effect of these drugs. Advanced glycation end-products in the form of glycated albumin stimulated PTECs to overexpress adhesion

The Kinin Receptor

The kallikrein–kinin system (KKS) has been associated with inflammation, coagulation, pain, and vascular permeability through the generation of kinins. Tissue kallikrein (KLK1), one of the components of KKS, is a serine protease that cleaves low–molecular weight kininogen into kinin, which exerts the biological functions through kinin receptor B1R and B2R signaling. The KKS has been shown to be involved in the pathogenesis of DN. HG induced KLK1 and B2R expression in cultured PTECs and in human

The Protease-Activated Receptor

Although most of the biological functions of KLK1 are mediated by kinin receptor signaling, recent studies suggest that KLK1 may also activate protease-activated receptors (PARs) in inflammatory and cardiovascular diseases.¹⁴ PARs are a subfamily of G protein–coupled receptors that are activated or inhibited by serine protease to expose a tethered ligand that binds to the receptor for signal transduction. There are four known members in the family, in which PAR-1 and PAR-3 are activated mainly

The Toll-Like Receptor

Toll-like receptors (TLRs) belong to the “interleukin-1 receptor/toll-like receptor superfamily,” which have the same cytoplasmic domain as the TIR (toll–IL-1 receptor) domain and share a similar pathway of activation. When activated, TLRs recruit different adapter molecules and then initiate diverse downstream signaling cascades including MyD88-dependent and independent pathways, resulting in engagement of transcription factors nuclear factor kappa-light-chain-enhancer of activated B (NF-κB),

Acknowledgments

This study was supported by a General Research Fund of the Research Grants Council (grant number: HKU 779611M) of Hong Kong, the National Basic Research Program of China 973 program no. 2012CB517600 (no. 2012CB517606), an Endowment Fund established for the “Yu Professorship in Nephrology” awarded to S.C.W.T., and the Hong Kong Society of Nephrology Research Grant 2010. W.H.Y. is partially supported by generous donations from Mr. Winston Leung, and the Hong Kong Concrete and the Continental

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Dysfunctional renal AQPs are correlated with impaired water stabilization including nephrogenic diabetes insipidus (NDI), autosomal dominant polycystic kidney disease (ADPKD) and acute kidney injury (AKI). Diabetic nephropathy (DN), a common complication of diabetic patients is a gradual accelerating disorder in which there is occurrence of impairment in renal function and is also one of the sole causes of end stage renal disease in adults.117 The expression of AQPs is impaired in DN patients as AQP5 is found to be overexpressed in their kidneys and as such the aforementioned AQP can serve as a potential biomarker of the disorder.118,119
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Our data suggest that glomerular injury during early diabetes appears to be related to NF-κB activation driven by TLR4 signaling and that the regulation of phosphorylation and localization of NF-κB is the mechanism through which ATRA exerts anti-inflammatory effect. Tubular cell hypertrophy is one of the early adaptive renal structural features in diabetes [40]. We have previously demonstrated tubular dysfunction and increased KIM-1 expression, a sensitive marker of tubular damage, at 3 weeks after STZ injection [4].
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: Financial Disclosure: See Acknowledgments on page 232.

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ICURT ProceedingsDiabetic Nephropathy and Proximal Tubular Damage

Section snippets

The Peroxisome Proliferator-Activated Receptor

The Kinin Receptor

The Protease-Activated Receptor

The Toll-Like Receptor

Acknowledgments

Kidney Int

Lancet

Lab Invest

J Biol Chem

Kidney Int

The pathogenic role of the renal proximal tubular cell in diabetic nephropathy

Nephrol Dial Transplant

Diabetic tubulopathy: an emerging entity

Contrib Nephrol

Activation of tubular epithelial cells in diabetic nephropathy and the role of the peroxisome proliferator-activated receptor-{gamma} agonist

J Am Soc Nephrol

Renoprotection by rosiglitazone in accelerated type 2 diabetic nephropathy: role of STAT1 inhibition and nephrin restoration

Am J Nephrol

The roles of Kruppel-like factor 6 and peroxisome proliferator-activated receptor-gamma in the regulation of macrophage inflammatory protein-3alpha at early onset of diabetes

Int J Biochem Cell Biol

ICURT Proceedings
Diabetic Nephropathy and Proximal Tubular Damage