Molecular mechanisms and therapeutic targets for diabetic kidney disease

Diabetic kidney disease has a high global disease burden and substantially increases the risk of kidney failure and cardiovascular events. Despite treatment, there is substantial residual risk of disease progression with existing therapies. Therefore, there is an urgent need to better understand the molecular mechanisms driving diabetic kidney disease to help identify new therapies that slow progression and reduce associated risks. Diabetic kidney disease is initiated by diabetes-related disturbances in glucose metabolism, which then trigger other metabolic, hemodynamic, inflammatory, and fibrotic processes that contribute to disease progression. This review summarizes existing evidence on the molecular drivers of diabetic kidney disease onset and progression, focusing on inflammatory and fibrotic mediators—factors that are largely unaddressed as primary treatment targets and for which there is increasing evidence supporting key roles in the pathophysiology of diabetic kidney disease. Results from recent clinical trials highlight promising new drug therapies, as well as a role for dietary strategies, in treating diabetic kidney disease. Diabetic kidney disease has a high global disease burden and substantially increases the risk of kidney failure and cardiovascular events. Despite treatment, there is substantial residual risk of disease progression with existing therapies. Therefore, there is an urgent need to better understand the molecular mechanisms driving diabetic kidney disease to help identify new therapies that slow progression and reduce associated risks. Diabetic kidney disease is initiated by diabetes-related disturbances in glucose metabolism, which then trigger other metabolic, hemodynamic, inflammatory, and fibrotic processes that contribute to disease progression. This review summarizes existing evidence on the molecular drivers of diabetic kidney disease onset and progression, focusing on inflammatory and fibrotic mediators—factors that are largely unaddressed as primary treatment targets and for which there is increasing evidence supporting key roles in the pathophysiology of diabetic kidney disease. Results from recent clinical trials highlight promising new drug therapies, as well as a role for dietary strategies, in treating diabetic kidney disease. Chronic kidney disease (CKD), characterized by albuminuria, low estimated glomerular filtration rate (eGFR), or both,1GBD Chronic Kidney Disease CollaborationGlobal, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet. 2020; 395: 709-733Abstract Full Text Full Text PDF PubMed Scopus (1156) Google Scholar is estimated to affect over 840 million people worldwide.2Jager K.J. Kovesdy C. Langham R. et al.A single number for advocacy and communication-worldwide more than 850 million individuals have kidney diseases.Kidney Int. 2019; 96: 1048-1050Abstract Full Text Full Text PDF PubMed Google Scholar Diabetic kidney disease (DKD), kidney damage due to diabetes, is the leading attributable cause of CKD, occurring in approximately 40% of people with type 2 diabetes (T2D) and 30% of those with type 1 diabetes (T1D).1GBD Chronic Kidney Disease CollaborationGlobal, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet. 2020; 395: 709-733Abstract Full Text Full Text PDF PubMed Scopus (1156) Google Scholar,3Alicic R.Z. Rooney M.T. Tuttle K.R. Diabetic kidney disease: challenges, progress, and possibilities.Clin J Am Soc Nephrol. 2017; 12: 2032-2045Crossref PubMed Scopus (753) Google Scholar The number of people with DKD is expected to increase in parallel with the rise in global diabetes prevalence,3Alicic R.Z. Rooney M.T. Tuttle K.R. Diabetic kidney disease: challenges, progress, and possibilities.Clin J Am Soc Nephrol. 2017; 12: 2032-2045Crossref PubMed Scopus (753) Google Scholar which is projected to increase by nearly 50%, from 537 to 783 million people, over the next 24 years.4International Diabetes FederationIDF Diabetes Atlas.10th ed. International Diabetes Federation, 2021Google Scholar The need is urgent to improve diagnosis and management of DKD, including better therapies that target disease mechanisms to slow progression to kidney failure and reduce related high cardiovascular (CV) risk.1GBD Chronic Kidney Disease CollaborationGlobal, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet. 2020; 395: 709-733Abstract Full Text Full Text PDF PubMed Scopus (1156) Google Scholar,3Alicic R.Z. Rooney M.T. Tuttle K.R. Diabetic kidney disease: challenges, progress, and possibilities.Clin J Am Soc Nephrol. 2017; 12: 2032-2045Crossref PubMed Scopus (753) Google Scholar Mechanisms of kidney damage in diabetes can be broadly classified as metabolic, hemodynamic, inflammatory, and fibrotic.3Alicic R.Z. Rooney M.T. Tuttle K.R. Diabetic kidney disease: challenges, progress, and possibilities.Clin J Am Soc Nephrol. 2017; 12: 2032-2045Crossref PubMed Scopus (753) Google Scholar,5Pérez-Morales R.E. Del Pino M.D. Valdivielso J.M. et al.Inflammation in diabetic kidney disease.Nephron. 2019; 143: 12-16Crossref PubMed Scopus (57) Google Scholar,6Mora-Fernández C. Domínguez-Pimentel V. de Fuentes M.M. et al.Diabetic kidney disease: from physiology to therapeutics.J Physiol. 2014; 592: 3997-4012Crossref PubMed Scopus (99) Google Scholar In this review, a current understanding of molecular mechanisms that drive DKD pathogenesis is presented as a basis for advancing therapeutic interventions. Hyperglycemia induces glomerular hyperfiltration and hypertension, hemodynamic mechanisms that have long been recognized to initiate and propagate kidney damage in diabetes.3Alicic R.Z. Rooney M.T. Tuttle K.R. Diabetic kidney disease: challenges, progress, and possibilities.Clin J Am Soc Nephrol. 2017; 12: 2032-2045Crossref PubMed Scopus (753) Google Scholar,6Mora-Fernández C. Domínguez-Pimentel V. de Fuentes M.M. et al.Diabetic kidney disease: from physiology to therapeutics.J Physiol. 2014; 592: 3997-4012Crossref PubMed Scopus (99) Google Scholar Glomerular hyperfiltration is exacerbated by high levels of amino acids, for example, after protein overfeeding, or with hormonal changes associated with poor glycemic control, for example, a high level of glucagon.7Rhee C.M. Kalantar-Zadeh K. Tuttle K.R. Novel approaches to hypoglycemia and burnt-out diabetes in chronic kidney disease.Curr Opin Nephrol Hypertens. 2022; 31: 72-81Crossref PubMed Scopus (0) Google Scholar, 8Tuttle K.R. Bruton J.L. Effect of insulin therapy on renal hemodynamic response to amino acids and renal hypertrophy in non-insulin-dependent diabetes.Kidney Int. 1992; 42: 167-173Abstract Full Text PDF PubMed Google Scholar, 9Tuttle K.R. Bruton J.L. Perusek M.C. et al.Effect of strict glycemic control on renal hemodynamic response to amino acids and renal enlargement in insulin-dependent diabetes mellitus.N Engl J Med. 1991; 324: 1626-1632Crossref PubMed Scopus (142) Google Scholar, 10Tuttle K.R. Puhlman M.E. Cooney S.K. Short R.A. Effects of amino acids and glucagon on renal hemodynamics in type 1 diabetes.Am J Physiol Renal Physiol. 2002; 282: F103-F112Crossref PubMed Google Scholar These circulating mediators of glomerular hyperfiltration primarily act by increasing perfusion through afferent arteriole dilation.3Alicic R.Z. Rooney M.T. Tuttle K.R. Diabetic kidney disease: challenges, progress, and possibilities.Clin J Am Soc Nephrol. 2017; 12: 2032-2045Crossref PubMed Scopus (753) Google Scholar,8Tuttle K.R. Bruton J.L. Effect of insulin therapy on renal hemodynamic response to amino acids and renal hypertrophy in non-insulin-dependent diabetes.Kidney Int. 1992; 42: 167-173Abstract Full Text PDF PubMed Google Scholar, 9Tuttle K.R. Bruton J.L. Perusek M.C. et al.Effect of strict glycemic control on renal hemodynamic response to amino acids and renal enlargement in insulin-dependent diabetes mellitus.N Engl J Med. 1991; 324: 1626-1632Crossref PubMed Scopus (142) Google Scholar, 10Tuttle K.R. Puhlman M.E. Cooney S.K. Short R.A. Effects of amino acids and glucagon on renal hemodynamics in type 1 diabetes.Am J Physiol Renal Physiol. 2002; 282: F103-F112Crossref PubMed Google Scholar In addition, activation of the renin angiotensin system is a key local trigger for glomerular hyperfiltration. Angiotensin II production within the kidney constricts the efferent arteriole, and thereby, contributes to higher glomerular pressure. Angiotensin II stimulates expression of proinflammatory and profibrotic mediators via this barotrauma and also by direct cellular effects.3Alicic R.Z. Rooney M.T. Tuttle K.R. Diabetic kidney disease: challenges, progress, and possibilities.Clin J Am Soc Nephrol. 2017; 12: 2032-2045Crossref PubMed Scopus (753) Google Scholar,6Mora-Fernández C. Domínguez-Pimentel V. de Fuentes M.M. et al.Diabetic kidney disease: from physiology to therapeutics.J Physiol. 2014; 592: 3997-4012Crossref PubMed Scopus (99) Google Scholar,10Tuttle K.R. Puhlman M.E. Cooney S.K. Short R.A. Effects of amino acids and glucagon on renal hemodynamics in type 1 diabetes.Am J Physiol Renal Physiol. 2002; 282: F103-F112Crossref PubMed Google Scholar The sodium-glucose cotransporter-2 (SGLT2) is now recognized as another important modulator of glomerular hemodynamics. It is expressed on the luminal surface of epithelial cells in the proximal convoluted tubule and is responsible for 90% of filtered glucose reabsorption.11Alicic R.Z. Neumiller J.J. Johnson E.J. et al.Sodium-glucose cotransporter 2 inhibition and diabetic kidney disease.Diabetes. 2019; 68: 248-257Crossref PubMed Scopus (55) Google Scholar,12Vallon V. Gerasimova M. Rose M.A. et al.SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice.Am J Physiol Renal Physiol. 2014; 306: F194-F204Crossref PubMed Scopus (318) Google Scholar In hyperglycemic conditions, SGLT2 expression and activity increase as an adaptation to reclaim glucose from the urine, but there is a maladaptive consequence of worsening hyperglycemia.11Alicic R.Z. Neumiller J.J. Johnson E.J. et al.Sodium-glucose cotransporter 2 inhibition and diabetic kidney disease.Diabetes. 2019; 68: 248-257Crossref PubMed Scopus (55) Google Scholar,13Heerspink H.J. Perkins B.A. Fitchett D.H. et al.Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications.Circulation. 2016; 134: 752-772Crossref PubMed Google Scholar Therapeutically, SGLT2 inhibition lowers blood glucose by decreasing glucose reabsorption at the proximal tubule resulting in glucosuria.13Heerspink H.J. Perkins B.A. Fitchett D.H. et al.Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications.Circulation. 2016; 134: 752-772Crossref PubMed Google Scholar In addition, SGLT2 inhibitors restore tubuloglomerular feedback by increasing distal delivery of sodium chloride to the macula densa, where solute reabsorption generates adenosine as a by-product of adenosine triphosphate utilization. Adenosine acts in a paracrine manner to enhance afferent arteriolar vasoconstriction, suppress renin release from juxtaglomerular cells, and perhaps reduce efferent arteriolar constriction.11Alicic R.Z. Neumiller J.J. Johnson E.J. et al.Sodium-glucose cotransporter 2 inhibition and diabetic kidney disease.Diabetes. 2019; 68: 248-257Crossref PubMed Scopus (55) Google Scholar,14Kidokoro K. Cherney D.Z.I. 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The tubular hypothesis of nephron filtration and diabetic kidney disease.Nat Rev Nephrol. 2020; 16: 317-336Crossref PubMed Scopus (102) Google Scholar The relative balance between increasing afferent and decreasing efferent arteriolar constriction in response to SGLT2 inhibition may vary by diabetes type and age. In physiological studies of humans with normal or high GFR, younger people with T1D demonstrated afferent arteriolar constriction, whereas older people with T2D had evidence of efferent arteriolar dilation.18van Bommel E.J.M. Lytvyn Y. Perkins B.A. et al.Renal hemodynamic effects of sodium-glucose cotransporter 2 inhibitors in hyperfiltering people with type 1 diabetes and people with type 2 diabetes and normal kidney function.Kidney Int. 2020; 97: 631-635Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Irrespective of the precise vasoregulatory mechanisms, on the whole, restoration of tubuloglomerular feedback reduces glomerular hypertension and, thereby, hyperfiltration.14Kidokoro K. Cherney D.Z.I. Bozovic A. et al.Evaluation of glomerular hemodynamic function by empagliflozin in diabetic mice using in vivo imaging.Circulation. 2019; 140: 303-315Crossref PubMed Scopus (124) Google Scholar,18van Bommel E.J.M. Lytvyn Y. Perkins B.A. et al.Renal hemodynamic effects of sodium-glucose cotransporter 2 inhibitors in hyperfiltering people with type 1 diabetes and people with type 2 diabetes and normal kidney function.Kidney Int. 2020; 97: 631-635Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Hyperglycemia prompts a series of intracellular processes that promote kidney damage via inflammation and fibrosis (Figure 1).3Alicic R.Z. Rooney M.T. Tuttle K.R. Diabetic kidney disease: challenges, progress, and possibilities.Clin J Am Soc Nephrol. 2017; 12: 2032-2045Crossref PubMed Scopus (753) Google Scholar,19Zhao L. Zou Y. Liu F. Transforming growth factor-beta1 in diabetic kidney disease.Front Cell Dev Biol. 2020; 8: 187Crossref PubMed Scopus (34) Google Scholar,20Reidy K. Kang H.M. Hostetter T. Susztak K. 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Genetics of diabetes mellitus and diabetes complications.Nat Rev Nephrol. 2020; 16: 377-390Crossref PubMed Scopus (163) Google Scholar Advances in acquiring large datasets in diabetes and genome-wide association studies have yielded new insights that shed light on predisposition to DKD. Missense mutations in the COL4A3 gene, which encodes a major structural component of the glomerular basement membrane (GBM), have long been known to cause Alport syndrome.48Salem R.M. Todd J.N. Sandholm N. et al.Genome-wide association study of diabetic kidney disease highlights biology involved in glomerular basement membrane collagen.J Am Soc Nephrol. 2019; 30: 2000-2016Crossref PubMed Scopus (55) Google Scholar Recently, another variant in COL4A3 (rs55703767) has been linked to protection from albuminuria or "diabetic nephropathy" in patients with T1D, suggesting that this variant may prevent disordered collagen expression.48Salem R.M. Todd J.N. 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Sandholm N. et al.Genome-wide association study of diabetic kidney disease highlights biology involved in glomerular basement membrane collagen.J Am Soc Nephrol. 2019; 30: 2000-2016Crossref PubMed Scopus (55) Google Scholar In contrast to protective genetic variants, APOL-l G1/G2 alleles observed in people of African ancestry promote development and progression of nondiabetic CKD, often when accompanied by a "second hit," for example, viral illness accompanied by a high interferon state.49Friedman D.J. Pollak M.R. APOL1 nephropathy: from genetics to clinical applications.Clin J Am Soc Nephrol. 2021; 16: 294-303Crossref PubMed Scopus (11) Google Scholar Another APOL-1 variant (rs9622363) has been recently reported to be associated with kidney failure in a large genome-wide association study meta-analysis of African American people with T2D, suggesting that it may increase the risk of DKD progression.50Guan M. Keaton J.M. 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